biomedicines

Review
Adipokines in Rheumatoid Arthritis: Emerging Biomarkers and
Therapeutic Targets
Jan Bilski 1, * , Agata Schramm-Luc 2 , Marian Szczepanik 3 , Agnieszka Irena Mazur-Biały 1 ,
Joanna Bonior 4 , Kevin Luc 2 , Klaudia Zawojska 1 and Joanna Szklarczyk 4

1 Department of Biomechanics and Kinesiology, Chair of Biomedical Sciences, Institute of Physiotherapy,

Faculty of Health Sciences, Jagiellonian University Medical College, 31-008 Krakow, Poland;
agnieszka.mazur@uj.edu.pl (A.I.M.-B.); klaudia.zawojska@uj.edu.pl (K.Z.)
2 Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical
College, 31-121 Krakow, Poland; agata.schramm@uj.edu.pl (A.S.-L.); kevin.luc1701@gmail.com (K.L.)
3 Chair of Biomedical Sciences, Institute of Physiotherapy, Faculty of Health Sciences, Jagiellonian University
Medical College, 31-034 Krakow, Poland; marian.szczepanik@uj.edu.pl
4 Department of Medical Physiology, Chair of Biomedical Sciences, Institute of Physiotherapy, Faculty of
Health Sciences, Jagiellonian University Medical College, 31-126 Krakow, Poland;
joanna.bonior@uj.edu.pl (J.B.); joannam.szklarczyk@uj.edu.pl (J.S.)
* Correspondence: jan.bilski@uj.edu.pl; Tel.: +48-12-421-93-51

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease manifested by joint involve-
ment, extra-articular manifestations, and general symptoms. Adipose tissue, previously perceived as
an inert energy storage organ, has been recognised as a significant contributor to RA pathophysiology.
Adipokines modulate immune responses, inflammation, and metabolic pathways in RA. Although
most adipokines have a pro-inflammatory and aggravating effect on RA, some could counteract this
pathological process. The coexistence of RA and sarcopenic obesity (SO) has gained attention due to
its impact on disease severity and outcomes. Sarcopenic obesity further contributes to the inflam-
matory milieu and metabolic disturbances. Recent research has highlighted the intricate crosstalk
between adipose tissue and skeletal muscle, suggesting potential interactions between these tissues
Citation: Bilski, J.; Schramm-Luc, A.; in RA. This review summarizes the roles of adipokines in RA, particularly in inflammation, immune
Szczepanik, M.; Mazur-Biały, A.I.; modulation, and joint destruction. In addition, it explores the emerging role of adipomyokines,
Bonior, J.; Luc, K.; Zawojska, K.; specifically irisin and myostatin, in the pathogenesis of RA and their potential as therapeutic tar-
Szklarczyk, J. Adipokines in gets. We discuss the therapeutic implications of targeting adipokines and adipomyokines in RA
Rheumatoid Arthritis: Emerging management and highlight the challenges and future directions for research in this field.
Biomarkers and Therapeutic Targets.
Biomedicines 2023, 11, 2998. Keywords: rheumatoid arthritis; adipokines; adipose tissue; skeletal muscle; myokines; inflammation;
https://doi.org/10.3390/ metabolism; therapeutic targets
biomedicines11112998

Academic Editor: Christa Büchler

Received: 22 October 2023

1. Introduction
Revised: 5 November 2023
1.1. Overview of Rheumatoid Arthritis
Accepted: 6 November 2023
Published: 8 November 2023 Rheumatoid arthritis (RA) is a systemic autoimmune disease accompanied by chronic
inflammation, leading to joint damage and extra-articular symptoms, which affects women
more than men. A characteristic of RA is the presence of synovitis, most often at the
level of small and medium joints, leading to symmetrical joint swelling and tenderness.
Copyright: © 2023 by the authors. Rheumatoid arthritis tends to fluctuate with periods of flare-ups and remission and, if
Licensee MDPI, Basel, Switzerland.
not well controlled, leads to progressive destruction of the joints [1–4]. Late diagnosis
This article is an open access article
of RA increases the risk of developing cancer and cardiovascular disease (CVD), reduces
distributed under the terms and
life expectancy, and is associated with poorer outcomes [1,2]. Individuals with RA are
conditions of the Creative Commons
more likely to have common risk factors associated with CVD, including hypertension,
Attribution (CC BY) license (https://
hyperlipidaemia, insulin resistance, and metabolic syndrome, which can be attributed to
creativecommons.org/licenses/by/
4.0/).
increased adipose tissue, altered body composition, and elevated levels of pro-inflammatory

Biomedicines 2023, 11, 2998. https://doi.org/10.3390/biomedicines11112998 https://www.mdpi.com/journal/biomedicines

Biomedicines 2023, 11, 2998 2 of 48

adipokines [5]. This increased risk for the development of comorbidities, particularly CVD,
is one of the most prevalent causes of morbidity and mortality in this patient population [6].
Although the exact aetiology of RA is not yet fully understood, a combination of
genetic and environmental factors is believed to play a significant role in its onset [1,2,7].
Rheumatoid arthritis is a chronic immune-mediated disorder in which numerous immune
cell types are activated, causing damage predominantly in the joints but also in the vascular
system and lungs [1,7,8]. Both Th1 and Th17 lymphocytes play an important role in the
pathogenesis of RA. Joint inflammation is the result of an interplay between adaptive
and innate immune cells, including T and B lymphocytes, fibroblasts, macrophages, den-
dritic cells (DC), neutrophils and osteoclasts [2]. Activated autoreactive Th1 and Th17
lymphocytes activate macrophages and fibroblasts in the affected joints via secreted tu-
mour necrosis factor alpha (TNFα), interleukin (IL) 17A, interferon gamma (IFN-γ), and
receptor activator of nuclear factor kappa-B ligand (RANKL). Additionally, autoreactive
T lymphocytes support autoreactive B cells in the production of anti-citrullinated protein
antibodies (ACPAs) and rheumatoid factor (RF) autoantibodies [7,8]. Rheumatoid arthritis
can be subdivided into two main subtypes based on the presence of RF and/or ACPAs [8].
The presence of RF or ACPAs is a poor prognostic factor and is an indication to introduce
biological treatment following ineffective initial treatment using a conventional synthetic
disease-modifying anti-rheumatic drug (csDMARD) [9].
Several studies have investigated environmental and lifestyle risk factors for RA.
Smoking, ozone exposure, and traffic-related air pollution have emerged as significant
contributors to RA susceptibility, especially in seropositive patients [10]. Specifically,
infections that involve the prevalent periodontal bacterium Porphyromonas gingivalis can
lead to the initiation of autoimmune responses through the citrullination process, wherein
both human and bacterial proteins are modified by protein arginine deiminase (PAD)
enzymes within the periodontium [11,12].
The expression of PAD by P. gingivalis allows the bacterium to breach local tolerance
by converting arginine to citrulline. This breach of tolerance can promote autoimmune
responses and the downstream generation of ACPAs [11,12]. It has also been suggested that
tobacco smoking predominantly contributes to the progression of rheumatoid arthritis by
influencing tissue protein citrullination [13]. Furthermore, there appears to be a potential
negative correlation between socioeconomic status and the risk of developing RA. Some
studies suggest a potential association between obesity and the development of RA, while
others present conflicting evidence, finding no such link [14]. The underlying reasons for
these disparities remain elusive, but it is conceivable that various factors such as age, sex,
and genetic background may influence the connection between obesity and RA. Notably,
the incidence of obesity has experienced a substantial upsurge in recent decades, giving rise
to concerns that it may contribute to the heightened prevalence of rheumatoid arthritis [14].
Hormonal factors, microbiome composition, and infectious agents may also contribute
to RA development [1,7,10,15,16]. In recent years, an increasing number of studies have
explored the intricate relationship between the composition of the gut microbiota and di-
etary patterns in RA patients. Evidence suggests that dietary factors substantially influence
the intricate makeup and dynamics of the human gut microbiota, potentially leading to
dysbiosis, which can alter immune regulatory functions and promote a pro-inflammatory
state [17–20].
Environmental factors upregulate the expression of PADs, which can modify peptides
by converting arginine to citrulline. After recognition of modified proteins presented by
antigen-presenting cells (APCs) such as DCs, T cells support the production of antibodies
directed against the altered peptides, including ACPAs. Autoreactive T and B cells initiate
an inflammatory cascade in synovial tissues, causing inflammation and damage to the
cartilage [21,22]. This leads to synovial enlargement, angiogenesis, osteoclast activation,
and bone degradation. Inflammatory cytokines induce the transformation of monocyte–
macrophage lineage cells into mature osteoclasts, causing bone resorption and erosion [21].
Biomedicines 2023, 11, 2998 3 of 48

During these processes, synovial macrophages release pro-inflammatory cytokines

such as TNFα, IL-1β, and IL-6, which stimulate the activity of osteoclasts and fibroblast-like
synoviocytes (FLS), leading to bone erosion. The synovium, located on the joint capsule’s
interior surface, is known to play a crucial role in the pathogenesis of RA. In healthy
individuals, the synovium is a thin, delicate tissue layer that lubricates and protects joints.
However, in patients with RA, the synovium undergoes inflammation, hyperplasia, and
thickening, resulting in synovitis and eventual joint destruction [23]. During the initial
stages of RA, the synovium undergoes inflammation due to leukocyte infiltration caused
by the activation of endothelial cells expressing adhesion molecules and chemokines [24].
The clinical phase of RA starts with the activation of the adaptive and innate immune
systems. Pro-inflammatory cytokines, such as IL-17A produced by Th17 cells and TNFα,
IL-1 β, and IL-6 secreted by macrophages, play a crucial role in the pathogenesis of RA [23].
Interleukin-17A is produced mainly by Th17 cells and induces the production of other
cytokines, such as IL-6 and TNFα, and chemokines (CCL20, CCL2 and CCL7), which
promote the recruitment of neutrophils and monocytes to inflammatory sites in the syn-
ovium. These cells release destructive matrix metalloproteinases (MMP), which contribute
to joint destruction and damage to surrounding tissues. Matrix metalloproteinase 3 plays a
pivotal role in cartilage destruction, while FLS secrete MMP1 and MMP9. Interleukin-17A
also promotes the proliferation and survival of FLS, which play a crucial role in bone and
cartilage destruction in RA [25]. Moreover, IL-17A induces the production of RANKL by
FLS and osteoblasts, leading to the differentiation and activation of osteoclasts, the cells
responsible for bone resorption. This process ultimately contributes to bone erosion in
RA [25].
Current evidence suggests that FLS are significant players in the development of
RA [26] and are crucial in maintaining the homeostasis of synovial fluid (SF) and extracel-
lular matrix (ECM) in healthy joints [27]. When exposed to pro-inflammatory cytokines
and chemokines, FLS can become activated and display increased proliferation, migration,
and production of inflammatory mediators and enzymes, contributing to joint degra-
dation [23,26]. Rheumatoid arthritis-fibroblast-like synoviocytes play a key role in the
development of the RA pannus, a mass of inflammatory, invasive synovial tissue responsi-
ble for the erosive damage seen in advanced RA [27]. In RA patients, the interface between
bone and pannus is populated with osteoclasts, which have been implicated in marginal
joint erosions, as evidenced by various animal models. The rheumatoid synovium is a rich
source of osteoclast precursors and factors that stimulate osteoclast activation [28].
Angiogenesis is essential for the expansion of the synovial lining and subsequent inva-
sion of the pannus. Vascular endothelial growth factor (VEGF) is a potent proangiogenic
cytokine which plays a central role in the angiogenic process in RA and is produced by
various cells within the synovium, including macrophages, FLS, and endothelial cells [29].
Activated FLS in the hyperplastic synovium also mediate cartilage invasion and de-
struction independently of hyperplastic synovial tissue, which has been attributed to a
combination of adhesion-facilitating factors and the production of proteases, particularly
MMP3. Adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1) and Vascu-
lar Cell Adhesion Molecule 1 (VCAM-1) facilitate the anchoring of RA-FLS to cartilaginous
ECM components. Cadherin-11 (CDH-11), expressed by RA-FLS, is relevant in cartilage
destruction [30]. Furthermore, FLS can interact with T cells, B cells, and macrophages in
the joint, amplifying the inflammatory response [23,26].
Disease-modifying antirheumatic drugs (DMARDs) are essential for the treatment
of RA and should be initiated as soon as the diagnosis is made. Conventional synthetic
(cs) DMARDs, usually methotrexate, are used in the first line of treatment. If treatment
with csDMARDs does not lead to the achievement of the treatment target, biological
(b)DMARDs acting via inhibition of TNFα, IL-6, CD20, or inhibiting T cell activation
should be introduced. Another therapeutic option is targeted synthetic (ts)DMARDs,
acting via inhibition of Janus kinases [9]. Despite the advances made by these treatments
in achieving disease remission and preventing joint damage, a significant number of RA
Biomedicines 2023, 11, 2998 4 of 48

patients do not respond adequately to current therapies [7]. Therefore, there is an urgent
and unmet need for novel drugs and therapeutic approaches.

1.2. Role of Adipose Tissue in RA Pathophysiology

Obesity is a major social issue due to its increasing prevalence and is usually defined as
a pathological or excessive accumulation of adipose tissue in the body, which is detrimental
to health [31]. Adipose tissue, which is made up of brown adipose tissue (BAT) and white
adipose tissue (WAT), plays a pivotal role in metabolism. Brown adipose tissue releases
stored energy as heat, whereas WAT stores excess energy as triglycerides [32,33]. Other
types of adipose tissue have recently been described [34–36]. Moreover, WAT and BAT
can regulate metabolism and communicate with other organs through the production of
lipokines, adipokines, and batokines, as well as exosomal miRNAs [36–38]. The dysfunction
of adipose tissue in obesity leads to chronic low-grade inflammation and a shift in adipokine
production towards a pro-inflammatory profile [39–41] associated with an increased risk
of metabolic and cardiovascular diseases and certain malignancies [42,43]. In addition,
obesity can contribute to the onset of inflammatory disorders [44,45].
Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), which have
different metabolic and immunological characteristics, are the two main anatomical com-
partments of WAT [46,47]. Accumulation of VAT is strongly associated with an increased
risk of metabolic and cardiovascular disorders and mortality [36,48–50]. Although SAT
may offer some health benefits, visceral fat accumulation, particularly in ectopic obesity,
such as perimuscular fat, may have detrimental effects [51,52].
While the primary focus of RA research has traditionally been on the synovium and
immune cells, growing evidence highlights the role of adipose tissue in RA pathophysiology.
Obesity can lead to mechanical stress on joints, especially weight-bearing joints such as
the knees, hips, and feet. In individuals with RA, obesity can exacerbate joint pain and
inflammation and contribute to disease progression and joint damage [53]. In the context of
obesity in RA, particularly if there is an accumulation of visceral fat, the production of pro-
inflammatory adipokines significantly increases the risk of cardiovascular complications [6].
Obesity, particularly visceral obesity, has been identified as a potential risk factor
for the development and progression of RA [54–66], specifically among women [60,63,66].
Recent meta-analyses have provided compelling evidence supporting a positive association
between obesity and RA, revealing a dose–response relationship between body mass index
(BMI) and RA risk [54,67,68]. This association appears to be more pronounced in women
and cases of seronegative disease. However, it is essential to note that the meta-analyses
on this subject have presented conflicting results, necessitating further investigation and
clarification [54,67,68].
Findings by Li et al. [69] provide valuable insight into the intricate interplay between
adipose tissue and the pathogenesis of RA. They studied the role of adipose tissue in
inflammatory arthritis by creating fat-free (FF) mice devoid of WAT and BAT but retaining
marrow adipocytes. They found that FF mice were resistant to K/BxN serum transfer
arthritis. In order to understand the underlying process, the researchers conducted genetic
deletion and fat transplantation studies [69]. These experiments demonstrated the crucial
involvement of adipsin, a factor unique to adipose tissue, in the pathogenesis of arthritis.
They concluded that adipose tissue plays a pivotal role in RA development, with adipsin
being the important link between adipose tissue and arthritis [69].
The therapeutic application of BAT in the treatment of autoimmune diseases may
have prospective benefits. Moon et al. [70] compared the BAT functions of mice with
collagen-induced arthritis (CIA) to those of healthy mice. They demonstrated that CIA
mice which had received BAT from healthy mice exhibited substantially reduced bone
damage, inflammation, and cartilage damage. Additionally, the levels of pro-inflammatory
cytokines, such as IL-6, IL-12, IL-17, and TNFα, were reduced in mice which had received
BAT from healthy mice. According to these findings, the transplantation of normal BAT
may have therapeutic significance in RA patients [70].
Biomedicines 2023, 11, 2998 5 of 48

In a murine CIA model of RA, pathological changes were observed in the thoracic
perivascular adipose tissue (PVAT) [71]. In humans, PVAT is the outermost layer of blood
vessels surrounding most conduit vessels. In a healthy state, PVAT primarily releases
anti-inflammatory molecules such as adiponectin, omentin, IL-10, nitric oxide (NO), and
fibroblast growth factor-21 (FGF21), contributing to vascular homeostasis [72]. How-
ever, in pathological conditions such as obesity, PVAT undergoes significant changes,
becoming predominantly composed of white adipocytes, and this results in the release
of pro-inflammatory adipokines such as leptin, visfatin, chemerin, resistin, apelin, TNFα,
monocyte chemoattractant protein-1 (MCP-1 or CCL2), IL-1β, IL-6, and IL-8 [72]. These
pathological alterations in PVAT have been implicated in the development of CVD in RA
patients [72].
However, not all observations support the link between high BMI and the development
of RA [73,74]. Some data unanimously show a surprisingly protective action of obesity
for radiographic joint damage in RA [75]. Possible explanations for this phenomenon
include stimulation of bone synthesis due to increased mechanical loading, greater levels
of oestrogens in obese patients known to exhibit bone-protective effects, as well as the
involvement of adiponectin [75]. Another reason for this discrepancy may be that RA is
associated with considerable alterations in body composition [76,77]. Body mass index
is a widely utilized indicator of obesity; however, it is not perfect because it does not
precisely reflect body fat distribution. A person with a normal BMI may have a high
percentage of VAT, which is linked to an increased risk of cardiometabolic diseases [78].
In addition, approximately 30% of obese individuals have a favourable metabolic profile,
meaning they do not have the metabolic complications typically associated with obesity [78].
The limitations of using BMI emphasise the need for improved methods of assessing body
fat content. Newer methodologies, such as body composition analysis, can provide more
exact measurements of body fat and its distribution [78].
Rheumatoid arthritis patients can have a condition known as sarcopenic obesity (SO),
wherein they have a lower skeletal muscle mass and higher body fat mass when compared
to healthy individuals [77]. The primary factor driving these changes is systemic inflam-
mation; however, several other factors, including malnutrition, physical disability, and
comorbidities, can also contribute to alterations in body composition in RA patients [77].
Treatment with corticosteroids and bDMARDs can influence body composition in RA
patients, including inhibition of the inflammatory process and causing an increase in BMI.
In particular, TNFα inhibitors have been shown to increase body weight and BMI as a
potential side effect. A systematic review and meta-analysis found evidence for a small
increase in body weight and BMI during treatment with TNFα inhibitors [79].
A comprehensive literature review by Letarouilly et al. [77] confirmed that RA is asso-
ciated with a reduction in lean muscle mass and an increase in adiposity, regardless of the
patient’s sex. Additionally, the prevalence of abnormal body composition conditions, such
as excessive fat accumulation, sarcopenia, SO, and rheumatoid cachexia, is significantly
greater among RA patients than among healthy individuals. Notably, these disturbances
in body composition are observed before the initiation of DMARDs [77]. These findings
highlight the importance of considering changes in body composition in the management
and treatment of RA.

1.3. Significance of Adipokines in RA

An abnormal profile of adipokines in the blood indicates adipose tissue dysfunction
in RA patients. Adipokines contribute to the pathogenesis of RA by influencing cartilage,
synovium, bone, and numerous immune cells [80] (Figure 1).
 1.3. Significance of Adipokines in RA
An abnormal profile of adipokines in the blood indicates adipose tissue dysfunction
in RA patients. Adipokines contribute to the pathogenesis of RA by influencing cartilage,
Biomedicines 2023, 11, 2998 6 of 48
synovium, bone, and numerous immune cells [80] (Figure 1).

Figure 1. Adipokines and adipomyokines associated with rheumatoid arthritis (RA). This figure lists
numerous adipokines and adipomyokines, along with their effects that may be related to RA. Created
Figure 1. Adipokines
withand adipomyokines
BioRender.com associated
(accessed on with rheumatoid arthritis (RA). This figure
15 October 2023).
lists numerous adipokines and adipomyokines, along with their effects that may be related to RA.
Several(accessed
Created with BioRender.com adipokines,onincluding leptin,
15 October adiponectin, and visfatin, have been shown
2023).
to be elevated in patients with RA [81–86]. In the affected joints of RA patients, FLS,
as well as osteoclasts, osteoblasts, and chondrocytes, produce several adipokines which
Several adipokines,
contributeincluding
to the uniqueleptin, adiponectin,
inflammatory and visfatin,
microenvironment [80,84,86].have been
Due to shown
alterations in to
systemicwith
be elevated in patients adipokine levels, their
RA [81–86]. Indiagnostic potential
the affected as biomarkers
joints has been suggested
of RA patients, FLS, as inwell
the context of rheumatic diseases [87]. The significance of adipokines in RA lies in their
as osteoclasts, osteoblasts, and chondrocytes, produce several adipokines which contrib-
potential to modulate the immune system and local cells in synovial tissue, cartilage, and
ute to the uniqueboneinflammatory
[80,84,86]. microenvironment [80,84,86]. Due to alterations in sys-
A study by Giles
temic adipokine levels, their diagnostic et al. [88] found that
potential asthe proportion ofhas
biomarkers adipose
beentissue macrophages
suggested in the
(ATMs), along with their characteristic crown-like structures, is elevated in the SAT of RA
context of rheumatic diseases [87]. The significance of adipokines in RA lies in their po-
patients when compared to patients without RA. These alterations in ATMs were associated
tential to modulatewiththe
the immune
presence ofsystem and local
autoantibodies, cells of
biomarkers insystemic
synovial tissue, cartilage,
inflammation, and insulinand
bone [80,84,86]. resistance (IR). In addition, the study [88] demonstrated that patients treated with DMARDs
and TNFα inhibitors had lower ATM levels than other RA patients, which indicates that
A study by Giles et al. [88] found that the proportion of adipose tissue macrophages
these medications might modulate the immune response and inflammation in adipose
(ATMs), along with their
tissue of RAcharacteristic
patients. crown-like structures, is elevated in the SAT of RA
patients when compared to patients without RA. These alterations in ATMs were associ-
1.4. Adipose Tissue–Skeletal Muscle Cross-Talk in RA
ated with the presence of autoantibodies, biomarkers of systemic inflammation, and insu-
The growing interest in changes in body composition associated with RA has high-
lin resistance (IR). In addition,
lighted the potentialthe studyof[88]
importance demonstrated
cross-talk that
between adipose patients
tissue treated
and skeletal with
muscle in
DMARDs and TNFα inhibitors
this disease had lower
[89]. Adipose ATM
tissue and levels
skeletal than
muscle other
are two RA
major patients,
organs that canwhich
actively in-
communicate and interact with each other via the secretion of various factors, such as
dicates that theseadipokines
medications might modulate the immune response and inflammation
and myokines, which play crucial roles in modulating systemic inflammation,
in adipose tissue of RAsensitivity,
insulin patients.and overall metabolic homeostasis [38,90,91]. Growing evidence shows
that skeletal muscle abnormalities and adipose tissue dysfunction are common in RA
1.4. Adipose Tissue–Skeletal Muscle Cross-Talk in RA
The growing interest in changes in body composition associated with RA has high-
lighted the potential importance of cross-talk between adipose tissue and skeletal muscle
Biomedicines 2023, 11, 2998 7 of 48

patients [81,89,92]. These alterations to adipose tissue contribute to the chronic low-grade
inflammation and metabolic disturbances seen in RA patients [81,93]. Simultaneously,
skeletal muscle abnormalities such as wasting, impaired muscle function, and reduced exer-
cise capacity are frequently observed in RA and contribute to diminished physical function
and quality of life [89,94]. It is clear that RA is a systemic disease where chronic inflam-
mation extends beyond the joints and affects multiple organ systems, including adipose
tissue and skeletal muscle [89,95]. Cross-talk between adipose tissue and skeletal muscle is
bidirectional, with adipose tissue-derived factors influencing muscle health and function
and muscle-derived factors affecting adipose tissue metabolism and inflammation. In RA,
dysregulation of this cross-talk may have deleterious effects on both adipose tissue and
skeletal muscle, thereby exacerbating the disease process and comorbidities [81,89,90,93,96].
Understanding the complex relationship between adipose tissue and skeletal muscle in
RA is crucial for the identification of novel therapeutic targets and interventions [77,97].
Targeting the factors implicated in fat–muscle cross-talk has the potential to reduce systemic
inflammation, improve metabolic abnormalities, preserve muscle mass and function, and
eventually enhance the overall management of RA [77,90,97,98].
Sarcopenia is defined by decreased skeletal muscle mass, strength, and function [89].
Although it is primarily associated with ageing, it can also occur in younger individuals
with autoimmune disorders such as RA. These patients have a substantial risk of developing
a condition known as rheumatoid sarcopenia, which is prevalent in over 25% of cases [77,97].
Chronic inflammation, driven by cytokines such as TNFα, IL-6, and IFN-γ, disrupts muscle
homeostasis and accelerates muscle protein breakdown, hindering muscle stem cell renewal
and impairing myofiber force [77,97]. This inflammatory burden sets RA apart from the
more age-related variant, as seen in animal models [99] and RA patients [100], where
skeletal muscle is a significant target of the inflammatory cascade.
Given its significant impact on mortality and disability, sarcopenia is of great clinical
importance. Historically, RA research has centred on rheumatic cachexia, a condition
marked by involuntary weight loss due to chronic illness. This state is characterised by
diminished muscle strength, anorexia, fatigue, a low fat-free mass index, and abnormal
blood parameters [89]. The traditional approach to investigating rheumatoid cachexia has
primarily revolved around RA patients with lower body mass. However, contemporary
studies have taken a new direction, exploring SO [101], which is characterised by reduced
muscle mass and increased adipose tissue mass, particularly VAT. Notably, SO is more
prevalent among individuals with RA than the general population, and its presence is
linked to a less favourable prognosis [101]. In RA patients, a reduction in muscle mass
may be accompanied by an increase in fat mass, which might result in the release of more
pro-inflammatory molecules from VAT that could negatively affect skeletal muscles [89,101].
Approximately 12.6% of patients with RA are afflicted by SO [101].
Skeletal muscle fat infiltration occurs more rapidly in RA patients, adversely affecting
muscle strength and physical performance [102]. Fat infiltration can affect skeletal muscle
contractility and function, leading to metabolic dysfunction through lipotoxicity and insulin
resistance [103]. Furthermore, intramuscular fat can release pro-inflammatory adipokines
that induce myocyte apoptosis and contribute to systemic inflammation [104–106].
The use of glucocorticoids as a therapeutic strategy to mitigate manifestations of
RA has been associated with the onset of sarcopenia [107]. Muscle proteolysis induced
by glucocorticoids is predominantly facilitated by the activation of catabolic pathways,
encompassing the ubiquitin–proteasome and autophagy–lysosomal systems. Furthermore,
glucocorticoids induce muscle atrophy by altering the expression of pivotal regulatory
factors involved in muscle development, such as insulin-like growth factor-I (IGF-I) and
myostatin (MSTN) [108–112]. Myostatin, a robust suppressor of muscle hypertrophy,
is upregulated by glucocorticoids, which subsequently instigate the phosphorylation of
Smad2/3 and inhibit Akt phosphorylation, culminating in muscle atrophy [111]. These
complex pathways are governed by specific transcription factors such as forkhead box O
(FoxO), which are phosphorylated and inactivated by Akt in the cytoplasm [111].
Biomedicines 2023, 11, 2998 8 of 48

Investigations into the correlation between glucocorticoid administration and sarcope-

nia in RA have yielded inconsistent results. A meta-analysis by Dao et al. [113] found that
in adults with RA, glucocorticoid use was positively associated with sarcopenia. However,
a recent meta-analysis by Tam et al. [114] did not identify a statistically significant rela-
tionship between baseline glucocorticoid administration and sarcopenia. Nevertheless, six
out of seven studies reported elevated rates of glucocorticoid administration among RA
patients with sarcopenia [8–13], with three studies indicating a significant difference [8,9,12].
While some studies have reported greater glucocorticoid doses in patients with sarcopenia
compared to those without it [115,116], a study conducted by Brance et al. [117] did not
identify an association between the cumulative dose of glucocorticoids and sarcopenia in
univariate analysis.
A recent analysis of data from the CHIKARA study supports the hypothesis that
glucocorticoids play a role in the development of rheumatoid sarcopenia [118]. Yamada et al.
discovered that RA patients using glucocorticoids at an average dose of 3.25 mg/day or
more for a year exhibited an increased risk of developing sarcopenia [118]. This observation
is consistent with findings from an animal study conducted on TNF-α transgenic mice
(TNF-tg). This study noted that muscle wasting was significantly augmented in animals
that received glucocorticoids [119].
The conflicting findings on the relationship between glucocorticoid use and sarcopenia
in RA patients underscore the need for further research in this area.
In their meta-analysis, Tam et al. [114] identified several studies that established a
correlation between sarcopenia and increased disease activity in RA patients [120–123].
Upon pooled analysis, this association was found to include greater DAS28 scores among
patients with sarcopenia [114]. The authors suggested that this correlation likely indicates a
bidirectional relationship, as heightened disease activity may trigger the onset of sarcopenia
through disability and inflammatory pathways [114,124]. The preliminary results of a
longitudinal study by Park and colleagues [125] suggest that sarcopenia may be predictive
of heightened disease activity in RA patients over a period of 3 years.
Sarcopenic obesity has been associated with poorer health outcomes when compared
to sarcopenia or obesity alone. Previous studies have linked SO to an increased risk of
cardiovascular disease, decreased bone mineral density, and heightened all-cause mor-
tality [126–128]. However, few clinical studies have directly compared health outcomes
between RA patients with SO versus those with sarcopenia or obesity alone. In a recent
study, Baker et al. [101] investigated the association between sarcopenia, obesity, and SO
and physical function and disability progression over time in RA patients. They found
that RA patients with SO showed greater rates of physical disability and more severe
progression of disability over time when compared to RA patients with sarcopenia or
obesity alone.
Considering the multifaceted factors contributing to the development of RA, the
implementation of a comprehensive therapeutic approach holds promise for enhancing
overall health and bolstering muscle strength and function. A combined strategy that
promotes physical activity and concurrently reduces systemic inflammation may offer
synergistic benefits (for detailed review, see Bennett et al. 2023) [89].
No approved pharmacological treatment for sarcopenia is available, but various com-
pounds have been investigated for their potential benefits to muscle health [129]. Several
studies have indicated that antagonization of MSTN, activin A, and GDF11 signalling is
a promising therapeutic approach for sarcopenia, and several smaller clinical trials have
demonstrated that inhibition of MSTN/ActRII signalling may help to improve muscle mass
in patients with muscle wasting [130]. Unfortunately, their effectiveness in RA patients
with sarcopenia is still unknown. There has been increasing interest into how DMARDs
affect muscle health in RA. While some studies have found these therapies to be effective,
several recent systematic reviews and meta-analyses included studies of bDMARDs and
reported no overall effect of these therapies on muscle mass [113,131–133].
Biomedicines 2023, 11, 2998 9 of 48

The observations outlined in this review underscore the potential of interventions

aimed at optimizing the endocrine profile of adipose tissue for practical clinical applications.
Physical exercise is crucial in the prevention of sarcopenia and sarcopenic obesity [134–138].
The complexity of these health benefits can be partially explained by the release of bioactive
substances into the bloodstream during exercise [138,139]. Resistance training promotes
satellite cell activation and muscle protein synthesis and is crucial in combating sarcopenia.
It enhances muscle mass and function by increasing muscle fibre size [140]. Systematic
resistance exercises lead to an increase in the size of muscle fibres, particularly fast-twitch
fibres [141], while aerobic exercise improves cardiovascular health, muscle oxidative capac-
ity, and body mass control and may help to preserve adipose tissue mass while mitigating
obesity [103,142–144]. Whole-body vibration, blood flow restriction (BFR), and neuromus-
cular electrical stimulation (NMES) are potential alternative treatments for sarcopenia,
warranting further research [145–147].
In 2018, the European League Against Rheumatism (EULAR) established safe and
practical physical activity guidelines for individuals with inflammatory arthritis [148].
Resistance training has been shown to improve the inflammatory state in RA patients, and
a systematic review reported significant improvements in muscle strength [149]. However,
the impact of various load masses and exercise modalities on muscle strength remains
unclear due to limited studies. While excessive training could exacerbate joint destruction
in RA patients [150], most studies suggest that moderate to high-intensity resistance train-
ing can be safely performed without worsening pain or disease activity [149,151]. Recent
studies have demonstrated the muscle-strengthening effects of moderate to high-intensity
training and suggest that a combination of resistance and aerobic exercises effectively im-
proves muscle strength and could reduce total and visceral fat in RA patients [149,152–158].
In a study by Rodrigues et al. [159], low-load resistance training with BFR was found to
effectively improve muscle strength in RA patients. Piva et al. [160] compared the effec-
tiveness of NMES and high-intensity volitional resistance training in improving muscle
structure and physical function in RA patients. Both methods were found to be effective,
with NMES suggested as a viable alternative for patients who may not tolerate high-
intensity resistance exercise.
A recent meta-analysis focusing on sarcopenia treatment in RA patients confirmed
that exercise therapy enhances muscle mass in these individuals. Moreover, RA patients
have shown positive responses and good tolerance to both resistance and non-resistance
exercise therapies [161]. Alterations in the secretory profile of adipokines and myokines
could partially explain the effect of exercise on muscle and adipose tissue. A recent study
discovered that 12 weeks of resistance exercise reduced serum leptin levels commensurate
with body fat mass or visceral fat area [157]. A recent animal study found that the increased
expressions of certain genes in muscle atrophy (MSTN, atrogin-1, MyoD, and myogenin)
in mice with experimental arthritis are restored back to control levels following acute
resistance exercise [162].
Moreover, nutrition plays a significant role in influencing the progression and out-
comes of inflammatory diseases such as RA. While research in this area is limited, some
studies have linked dietary factors, including fatty acids, probiotics, and anti-inflammatory
diets, to improved RA symptoms and daily functioning [163]. The impact of nutritional
interventions on rheumatoid sarcopenia is discussed in detail in a recent review by Cruz-
Jentoft et al. [164].
A comprehensive approach combining physical activity promotion, systemic inflam-
mation reduction, nutritional interventions, and alternative treatments could potentially
offer an effective strategy for managing rheumatoid sarcopenia. However, more research is
needed to fully understand the impact of these interventions.
This review will assess the contribution of adipokines to the onset and progress of
RA, with particular emphasis on the most extensively researched molecules in this field.
Specifically, we will assess the current understanding of the role of adipokines in the
pathogenesis of RA and their mechanisms of action in promoting inflammation and joint
 Specifically, we will assess the current understanding of the role of adipokines in the path-
ogenesis of RA and their mechanisms of action in promoting inflammation and joint de-
struction. In addition, we will evaluate the potential of adipokines and adipomyokines as
biomarkers for RA diagnosis, disease activity, prognosis, and the correlation between
Biomedicines 2023, 11, 2998 10 of 48
their serum and synovial fluid (SF) concentrations and disease severity and joint damage.
Furthermore, we will investigate the therapeutic potential of targeting specific adi-
pokines and adipomyokines in the management of RA, focusing on strategies helping to
destruction. In addition, we will evaluate the potential of adipokines and adipomyokines
reduce muscle wasting, improve
as biomarkers metabolic
for RA diagnosis,regulation, andprognosis,
disease activity, modulate andthe
the inflammatory
correlation between
milieu. Moreover, their
we will
serumidentify the challenges
and synovial and opportunities
fluid (SF) concentrations and diseaseassociated with
severity and trans-
joint damage.
Furthermore, we will investigate the therapeutic potential of targeting
lating adipokine-based therapies into clinical practice, taking into account patient hetero- specific adipokines
and adipomyokines in the management of RA, focusing on strategies helping to reduce
geneity and developing targeted delivery techniques for specific tissues. By addressing
muscle wasting, improve metabolic regulation, and modulate the inflammatory milieu.
these research objectives,
Moreover,this
wereview aimsthe
will identify tochallenges
shed lightand onopportunities
the complexassociated
interplay between
with translating
adipokines, adipomyokines,
adipokine-basedand RA pathogenesis,
therapies highlighting
into clinical practice, taking into their
accountpotential as bi-
patient heterogeneity
omarkers and therapeutic targets.
and developing Ultimately,
targeted deliverythis review for
techniques aims to contribute
specific tissues. Bytoaddressing
the devel- these
research objectives, this review aims to shed light
opment of personalised and efficient management strategies for RA patients. on the complex interplay between
adipokines, adipomyokines, and RA pathogenesis, highlighting their potential as biomark-
ers and therapeutic targets. Ultimately, this review aims to contribute to the development
2. Adipokines in Rheumatoid
of personalised Arthritis
and efficient management strategies for RA patients.
In rheumatic diseases, adipose tissue is not the sole source of adipokines. Other cell
2. Adipokines in Rheumatoid Arthritis
types, including chondrocytes and synoviocytes, also produce these mediators [87]. In
In rheumatic diseases, adipose tissue is not the sole source of adipokines. Other
musculoskeletal disorders, adipokines
cell types, including target cells
chondrocytes andand tissues such
synoviocytes, alsoas bones,these
produce cartilage, and[87].
mediators
the synovial membrane via autocrine,
In musculoskeletal paracrine,
disorders, andtarget
adipokines endocrine
cells andpathways
tissues suchand playcartilage,
as bones, im-
portant roles in the pathogenesis of the disease [86,87]. Studies have reported elevatedplay
and the synovial membrane via autocrine, paracrine, and endocrine pathways and
important
levels of adipokines in both roles in theand
serum pathogenesis
SF fromofRA the patients
disease [86,87].
whenStudies have reported
compared elevated
to healthy
levels of adipokines in both serum and SF from RA patients when compared to healthy
controls [165–167]controls
(Figure[165–167]
2). (Figure 2).

Figure 2. Levels of adipokines and adipomyokines in serum/plasma and synovial fluid in rheumatoid
Figure 2. Levels of adipokines and adipomyokines in serum/plasma and synovial fluid in rheuma-
arthritis (RA), and their correlation with disease activity. This figure illustrates the changes in
toid arthritis (RA), and their correlation with disease activity. This figure illustrates the changes in
serum/plasma and synovial fluid levels of various adipokines and adipomyokines in RA, represented
serum/plasma and synovial fluid levels of various adipokines and adipomyokines in RA, repre-
by upward (elevated levels) and downward (reduced levels) arrows. The figure also indicates the
sented by upward (elevated levels) and downward (reduced levels) arrows. The figure also indi-
correlation of these substances with disease activity, denoted by a plus sign (positive correlation),
cates the correlationminus
of these substances with disease
sign (negative correlation), activity,
or zero denoted by
(no correlation). a plus sign
A question mark(positive
is used tocor-
indicate
relation), minus signconflicting
(negative correlation),
or uncertain or zero
data. This (no correlation).
comprehensive A question
diagram aims mark
to elucidate is usedrelationships
the complex to in-
dicate conflicting orbetween
uncertainthesedata. This
bioactive comprehensive
molecules, diagram
their systemic aims
and local toand
levels, elucidate
RA disease theactivity.
complex Created
relationships between withthese bioactive(accessed
BioRender.com molecules,
on 17 their
Octobersystemic
2023). and local levels, and RA disease
activity. Created with BioRender.com (accessed on 17 October 2023).
However, Presle et al. [168] demonstrated that serum levels of adipokines do not serve
as predictive markers for determining the concentration of adipokines in the SF. Moreover,
However, Presle et al. [168] demonstrated that serum levels of adipokines do not
their findings indicate that levels of adipokines within the synovial joint are regulated
serve as predictive markers for
independently determining
of the serum [168].the concentration of adipokines in the SF.
Moreover, their findings indicate
In recent years,that
therelevels ofincreasing
has been adipokines within
interest the synovial
in exploring joint
adipokines are
as potential
therapeutic targets and
regulated independently of the serum [168].biomarkers in RA [80,169].
In recent years, there has been increasing interest in exploring adipokines as potential
therapeutic targets and biomarkers in RA [80,169].
Biomedicines 2023, 11, 2998 11 of 48

2.1. Leptin
Leptin was identified as the first adipokine, and it is predominantly secreted by WAT,
with fluctuating levels throughout the day. The blood concentration of this hormone is
proportional to the amount of adipose tissue in the body [170]. Leptin regulates energy
balance and food intake by binding to functional receptors encoded by the diabetes (db)
gene [170–172]. Leptin receptors (LepR) are class 1 cytokine receptors and are expressed by
most of the immune cells. Signal transducers, such as Janus kinases (JAK), signal transduc-
ers and transcription activators (STAT), phosphatidylinositol 3-kinase (PI3K), and mitogen-
activated protein kinase (MAPK), are activated when leptin binds to LepR [170,172]. Leptin
has pleiotropic effects, influencing both adaptive and innate immunity [170,171].
Leptin plays a substantial role in the aetiology of RA, according to studies primarily
conducted in mouse and rat models. Leptin was overexpressed in the SF of rats with
experimental antigen-induced arthritis (AIA) [173]. In a study by Otvos et al. [174], the
administration of leptin alone did not elicit arthritis in rats; however, it did exacerbate
the clinical condition of mice subjected to K/BxN serum transfer arthritis. When rats
in the same study received leptin receptor antagonists, leptin-induced disease activity
was attenuated [174]. Another study in a murine model of CIA showed a significant
increase in leptin levels in both joint tissue and SF compared to the control group. Upon
injecting leptin into the knee joint of collagen-immunised mice, the onset of arthritis
accelerated significantly, resulting in exacerbation of clinical symptoms and a notable
increase in synovial hyperplasia, joint degeneration, and abundance of Th17 cells in the
joint tissue [175].
Research conducted by Busso et al. [176] indicated that leptin-deficient (ob/ob) mice
with AIA had lower levels of synovial inflammation and production of pro-inflammatory
cytokines when compared to the control group. These findings suggest that leptin sig-
nalling contributes to the augmentation of synovial inflammation. On the other hand,
in the proliferative arthritis model of zymosan-induced arthritis (ZIA), leptin appears
to have a different function, as histopathology showed that ob/ob mice and mice with
leptin receptor deficiency (db/db) had delayed arthritis resolution and more joint damage
than controls [177]. High-fat diet (HFD)-induced obese mice which had CIA developed
peripheral leptin resistance, reducing the severity and inflammation [178].
Identification of leptin receptors in FLS is consistent with the hypothesis that leptin
plays a significant role in the pathogenesis of RA [179]. Specifically, leptin treatment led
to increased IL-8 production in FLS, further indicating its pro-inflammatory effects in RA.
The signalling pathways involved in this process include JAK2/STAT3, IRS-1/PI3K, Akt,
and NF-κB, as well as the recruitment of p300, which is known to promote inflammation and
may play an important role in the pathogenesis of RA [179]. Fibroblast-like synoviocytes
migrate to unaffected joints, which contributes to the spread of RA [180]. Interestingly,
leptin can induce the migration of FLS and angiogenesis by generating reactive oxygen
species (ROS) [181] (Figure 3). Moreover, TNFα, IL-6, and IL-1β antagonists have been
shown to attenuate leptin-induced ROS generation and FLS migration [181].
Expression of the LEPRb receptor in human chondrocytes provides compelling ev-
idence of leptin’s influence on chondrocyte function [182,183]. Interestingly, the admin-
istration of exogenous leptin in rat knee joints elicited phosphorylation of STAT1 and
STAT5 in chondrocytes, accompanied by increased proliferation and proteoglycan secre-
tion [184]. Such observations suggested that elevated leptin levels may confer short-term
protection against cartilage degradation [184,185]. However, prolonged exposure of human
chondrocytes to leptin, as typically seen in obesity, has been associated with diminished
cell viability [183,186,187]. In particular, up-regulation of LEPRb in leptin-treated human
chondrocytes triggers mTOR activation, leading to altered cell proliferation and induction
of cell senescence [188]. It was suggested that sustained activation of the leptin pathway
in chondrocytes could contribute to cartilage degradation, while transient and low-level
activation may exert a protective effect [183].
x FOR PEER REVIEW 12 of 51
Biomedicines 2023, 11, 2998 12 of 48

Figure 3. Schematic illustration of the role

Figure 3. Schematic of adipokines
illustration of the roleand adipomyokines
of adipokines in the pathogenesis
and adipomyokines of
in the pathogenesis
rheumatoid arthritis. ofTNFα: Tumour
rheumatoid Necrosis
arthritis. TNFα:Factor alpha;
Tumour IL-1β:Factor
Necrosis Interleukin-1 beta;
alpha; IL-1β: IL-6: Interleu-
Interleukin-1 beta; IL-6:
Interleukin-6;
kin-6; IL-8: Interleukin-8; IL-8: Interleukin-8;
IL-10: Interleukin-10; IL-10:Interleukin-12;
IL-12: Interleukin-10; IL-12: Interleukin-12;
IL-1Ra: IL-1Ra:
Interleukin-1 Interleukin-1
Receptor
Antagonist; TGF Beta: Receptor Antagonist;
Transforming TGF Beta:
growth Transforming
factor beta; OPG: growth factor beta; OPG:
Osteoprotegerin; Osteoprotegerin;
CCL2: C-C motifCCL2:
C-C motif chemokine ligand 2; CCL20: Chemokine (C-C
chemokine ligand 2; CCL20: Chemokine (C-C motif) Ligand 20; MCP-1: Monocyte Chemoattractantmotif) Ligand 20; MCP-1: Monocyte
Chemoattractant Protein-1; ADAMTS-4: A Disintegrin and Metalloproteinase with Thrombospondin
Protein-1; ADAMTS-4: A Disintegrin and Metalloproteinase with Thrombospondin Motifs 4;
Motifs 4; ADAMTS-7/12: A Disintegrin and Metalloproteinase with Thrombospondin Motifs 7/12;
ADAMTS-7/12: A Disintegrin and Metalloproteinase with Thrombospondin Motifs 7/12; MMPs:
MMPs: Matrix Metalloproteinases; TRAP: Tartrate-Resistant Acid Phosphatase; NOS-2: Nitric Oxide
Matrix Metalloproteinases; TRAP: Tartrate-Resistant Acid Phosphatase; NOS-2: Nitric Oxide Syn-
Synthase 2; PGE2: Prostaglandin E2; ROS: Reactive Oxygen Species; VCAM-1: Vascular Cell Adhesion
thase 2; PGE2: Prostaglandin E2; ROS: Reactive Oxygen Species; VCAM-1: Vascular Cell Adhesion
Molecule-1; VEGF: Vascular Endothelial Growth Factor; FLS: Fibroblast-like synoviocytes. Created
Molecule-1; VEGF: Vascular Endothelial
with BioRender.com Growth
(accessed Factor;
on 15 OctoberFLS: Fibroblast-like synoviocytes. Created
2023).
with BioRender.com (accessed on 15 October 2023).
Leptin plays a role in the induction of chondrocyte apoptosis through its upregula-
tion of
Expression of the LEPRb LOXL3, activation
receptor inofhuman
the mTOR pathway, andprovides
chondrocytes inhibition compelling
of autophagy evi-
[189,190].
Furthermore, leptin stimulates the production of MMPs and pro-inflammatory mediators
dence of leptin’s influence onTNFα,
such as IL-1, chondrocyte function
IL-6, IL-8, and MCP-1 by [182,183]. Interestingly,
chondrocytes. the the
It also promotes admin-
expression
istration of exogenous leptin in rat knee joints elicited phosphorylation of
of adhesion molecules, including VCAM-1, contributing to cartilage degradation STAT1 and[191].
STAT5 in chondrocytes, accompanied
Moreover, by increased
leptin can contribute to theproliferation
inflammatory and proteoglycan
process secre-acting
by synergistically
tion [184]. Such observations suggested that elevated leptin levels may confer short-termfrom
with IL-1 to induce joint inflammation through the release of NOS type II (NOS2)
chondrocytes [192].
protection against cartilage degradation [184,185]. However, prolonged exposure of hu-
Leptin exerts its effects through local and central pathways in the regulation of bone
man chondrocytes homeostasis.
to leptin, asNotably,
typically
Ducyseen
et al.in obesity,
[193] hasanbeen
conducted associated
experiment withordimin-
with ob/ob db/db mice
ished cell viability and
[183,186,187].
hypothesised Inthatparticular,
leptin acts asup-regulation
a potent inhibitorof LEPRb
of bone in leptin-treated
formation through the central
human chondrocytes nervous system.
triggers These activation,
mTOR observations have
leadingbeento
validated
alteredbycell
subsequent researchand
proliferation [194,195].
Pogoda et al. [196] found that intracerebroventricular (ICV) administration of leptin in
induction of cell senescence [188]. It was suggested that sustained activation of the leptin
sheep led to significantly decreased osteoblast activity and trabecular bone mass. On
pathway in chondrocytes
the othercould contribute
hand, leptin inhibitsto cartilage
osteoclast degradation,
differentiation while transient
in peripheral and
blood mononuclear
low-level activationcells
may exert aand
(PBMCs) protective effect
murine spleen [183].
cells cultured on bone substrates. This inhibiting effect
Leptin plays a role in the induction of chondrocyte apoptosis through its upregula-
tion of LOXL3, activation of the mTOR pathway, and inhibition of autophagy [189,190].
Furthermore, leptin stimulates the production of MMPs and pro-inflammatory mediators
such as IL-1, TNFα, IL-6, IL-8, and MCP-1 by chondrocytes. It also promotes the expres-
Biomedicines 2023, 11, 2998 13 of 48

is predominately mediated by the RANKL/RANK/OPG pathway, thereby substantially

contributing to the suppression of bone resorption [197]
Elevated serum leptin in RA patients, when compared to healthy individuals, has been
well established in numerous studies [85,167,198–206] (Table 1) and subsequently supported
by meta-analyses [83,207]. Furthermore, leptin levels in the SF of RA patients were greater
than in healthy controls [165,203] and individuals with osteoarthritis (OA) [198,199]. Leptin
levels in SF are believed to result from the diffusion of adipokine from the circulation into
the synovial tissue. However, recent studies in human chondrocytes have shown that these
cells can produce leptin and express its long receptor, suggesting that this molecule may
have a local function [208].

Table 1. Association of leptin and rheumatoid arthritis in humans.

Reference Subjects Results/Outcomes

No differences were observed in serum leptin levels between RA
58 RA patients
Anders et al. (1999) [209] patients and healthy controls.
16 controls without RA
No correlations existed between serum leptin levels and DAS.
Plasma levels in RA patients were significantly greater than
76 RA patients in controls.
Bokarewa et al. (2003) [198]
34 controls without RA Leptin levels in RA patients were significantly greater in plasma
than in SF samples,
No differences between RA patients and healthy controls in
31 RA patients plasma leptin levels were observed.
Popa et al. (2005) [210]
19 controls without RA In RA patients, plasma leptin levels were inversely correlated
with CRP and IL6 levels.
No significant difference between RA patients and the control
41 RA patients group was observed in plasma leptin levels.
Hizmetli et al. (2005) [211]
25 controls without RA No correlation was observed between serum leptin level and
disease duration, ESR, or CRP in RA patients.
Leptin serum levels in RA patients were significantly greater than
31 RA patients in controls.
Otero et al. (2006) [200]
18 controls without RA A positive correlation was observed between serum leptin and
CRP levels.
Serum leptin levels were greater in RA patients than in controls.
50 RA patients No correlations existed between serum leptin levels and disease
Gunaydin et al. (2006) [212]
34 controls without RA duration, swollen and tender joint counts, DAS28, CRP, ESR, and
serum TNFα levels.
Serum leptin levels were greater in RA patients with DAS28 > 3.2.
Lee et al. (2007) [213] 50 RA patients There was a positive correlation between serum leptin levels and
DAS28 and CRP.
There were no significant differences in serum leptin levels
between RA and OA patients.
Wislowska et al. (2007) [214] 30 RA patients, 30 OA patients No correlation existed between serum leptin level and disease
duration, duration of morning stiffness, and DAS28 in
RA patients.
Serum and SF leptin levels were significantly greater in RA
patients than in the control group.
20 RA patients
Seven et al. (2009) [215] RA patients with moderate disease activity (DAS > 2.7) had
25 controls without RA
significantly greater leptin levels than those with low disease
activity (DAS < 2.7)
Plasma leptin levels in RA patients were significantly greater than
52 RA patients in controls.
Canoruç et al. (2009) [216]
52 controls without RA Plasma leptin level significantly correlated with ESR and swollen
and tender joint count.
Biomedicines 2023, 11, 2998 14 of 48

Table 1. Cont.

Reference Subjects Results/Outcomes

Targonska-Stepniak et al. A positive correlation existed between leptin levels and
80 RA patients
(2010) [217] the DAS28.
Serum leptin levels were greater in RA patients than in controls.
40 RA patients
Ismail et al. (2011) [218] A positive correlation was observed between serum leptin levels
30 controls without RA
and the DAS28.
141 RA patients A positive correlation was observed between serum leptin and
Yoshino et al. (2011) [219]
146 controls without RA CRP levels.
Leptin serum levels in RA patients were significantly greater than
in controls.
Serum leptin level and synovial/serum leptin ratio significantly
correlated with the RA duration, DAS28, ESR, CRP, TNFα,
40 RA patients and IL-6.
Olama et al. (2012) [203]
30 controls without RA The serum leptin and the synovial/serum leptin ratio were
significantly greater in women than in men and in erosive RA
than non-erosive RA.
The synovial/serum leptin ratio was positively associated with
erosion in patients with RA.
Serum leptin levels were greater in RA patients than in controls.
37 RA patients There was no correlation between serum leptin level and disease
Allam et al. (2012) [220]
34 controls without RA duration, duration of morning stiffness, VAS, number of swollen
and tender joints, DAS28, ESR or CRP in patients with RA.
54 RA patients (29 with The two groups had no significant differences in mean serum
Mirfeizi et al. (2014) [221]
erosion, 25 without erosion) leptin levels.
60 RA patients Serum leptin levels were greater in RA patients than in controls.
Abdalla et al. (2014) [222]
30 controls without RA No correlation between leptin levels and the DAS28.
Bustos Rivera-Bahena et al. A positive correlation existed between leptin serum levels and
121 RA patients
(2015) [223] disease activity.
106 RA patients There were no differences in serum leptin levels between groups.
Oner et al. (2015) [224] 52 healthy controls No correlation was observed between serum leptin levels
37 OA patients and DAS28.
Serum leptin levels were greater in RA patients than in controls.
55 RA patients,
Dervisevic et al. (2018) [205] A positive correlation existed between leptin serum levels
25 controls without RA
and DAS28.
54 RA patients,
Wang et al. (2018) [204] Serum leptin levels were greater in RA patients than in controls.
46 controls without RA
136 RA patients
Chihara et al. (2020) [167] Serum leptin levels were greater in RA patients than in controls.
78 controls without RA
51 eRA patients Serum leptin levels were significantly greater in patients with
Rodriguez et al. (2021) [225]
51 controls without RA eRA than in healthy controls.
RA = rheumatoid arthritis; eRA= early RA; OA = osteoarthritis; CRP = C-reactive protein; TNFα = tumour
necrosis factor-α; IL-6 = Interleukin-6; ESR = erythrocyte sedimentation rate; DAS = Disease Activity Score;
DAS28 = DAS28 = Disease Activity Score 28; VAS = visual analogue scale, SF = synovial fluid.

While some studies have reported a correlation between circulating leptin levels and
disease activity markers such as C-reactive protein (CRP) and DAS28 [82,205,209,213,218,
223,226–233], not all investigations support these associations [220,222,224]. In their meta-
analysis, Lee et al. [82] concluded that a modest yet statistically significant correlation exists
between leptin levels and disease activity parameters such as DAS28 and CRP. However,
contrasting findings were reported by Hizmetli et al. [211], who found no statistically
significant differences in plasma and SF leptin levels between RA patients and healthy
controls. Additionally, they observed no correlation between leptin levels and disease du-
ration, erythrocyte sedimentation rate (ESR), CRP, or erosive/non-erosive RA. In addition,
Biomedicines 2023, 11, 2998 15 of 48

Popa et al. [210] found an inverse correlation between plasma leptin concentrations and
inflammatory markers in RA patients, indicating that chronic inflammation can inhibit
leptin production (Table 1).
Recently, the possible involvement of leptin in the pathogenesis of joint erosions
in RA has generated significant interest. Numerous research studies have elucidated
this issue, revealing notable differences in leptin levels among patients diagnosed with
erosive RA compared to those with non-erosive RA. The individuals with RA had notably
elevated leptin levels in SF, although no significant difference was identified in plasma
concentrations [198,199,217]. In addition, Olama et al. [203] found that the SF/serum ratio
was significantly greater in RA patients with radiologic erosions, further supporting this
observation. Based on these findings, the authors hypothesised that this decrease in serum
leptin level could be due to local leptin uptake, supporting the hypothesis that leptin may
play a protective role in the joint erosive process [203].
The multi-biomarker disease activity (MBDA) score, which includes 12 serum proteins,
strongly predicts radiographic deterioration in RA. Leptin-adjusted MBDA scores were
investigated in a recent study [234], and it was demonstrated that they were associated
with clinical disease activity and predicted radiographic progression of RA better than
the original score and other markers of disease activity [234,235]. Leptin antagonists have
been proposed as potential preventative treatments for RA, offering a new avenue for
personalised management of individuals at risk for developing RA, aiming to dampen the
inflammatory cascade and mitigate the onset and impact of this disease [236,237]. Further
research and clinical trials are needed to assess the safety and efficacy of these agents as a
preventative approach.
The role of leptin in RA is not only associated with articular tissues; it might also
have a potent effect on cell-mediated immune function (for review, see Wang et al., 2021,
Tsuchiya and Fujio, 2022) [191,238].

2.2. Adiponectin
Adiponectin is a secretory protein with a molecular weight of 28–30 kDa; it is primarily
produced by white adipocytes, encoded by the ADIPOQ gene and has multiple biologi-
cal functions [239,240]. Adiponectin has also been found in various cell types, including
osteoblasts, liver parenchyma cells, myocytes, endothelial cells, and the placenta [239].
It exists in three different isoforms based on its oligomerisation: low molecular weight
(LMW), medium molecular weight (MMW), and high molecular weight (HMW). The MMW
hexamers and HMW multimers are the most common forms found in the bloodstream,
while monomers and LMW isoforms are present at low levels or not detected in circulation.
Proteolytic cleavage of fibrous adiponectin produces globular adiponectin (gAPN), which
may have its own biological activities. The HMW isoform of adiponectin is considered
the most important physiologically and is increasingly used as a marker of adipocyte
dysfunction related to pathological states [239–241]. Adiponectin binds to two main recep-
tors, AdipoR1 and AdipoR2, which are distributed differently in various tissues. AdipoR1
activates AMP kinase, while AdipoR2 activates peroxisome proliferator-activated receptor
alpha (PPARα), promoting fatty acid oxidation and glucose metabolism. Adiponectin has
several biological functions, including stimulating fatty acid biosynthesis, inhibiting gluco-
neogenesis in the liver, and potentially affecting glucose uptake in skeletal muscles through
signalling pathways. It improves insulin resistance by promoting fatty acid oxidation
through the activation of PPARα and enhancing IRS signalling in skeletal muscle and liver.
Additionally, adiponectin has anti-inflammatory and anti-atherosclerotic effects [239–241].
In contrast to leptin, individuals with obesity, type 2 diabetes (T2D), and metabolic syn-
drome have decreased adiponectin levels. The anti-inflammatory properties of adiponectin
contribute to its beneficial effects on cardiovascular and metabolic disorders such as
atherosclerosis and insulin resistance [242]. On the other hand, pro-inflammatory effects of
adiponectin have been observed in conditions such as rheumatoid arthritis. However, the
Biomedicines 2023, 11, 2998 16 of 48

precise measurement of adiponectin isoforms and the lack of a universal standard have
posed challenges in understanding these phenomena [239–241].
Adiponectin exhibits a multifaceted involvement in RA. In a CIA mouse model, in-
hibiting adiponectin led to reduced joint swelling and bone destruction and decreased
expression of angiogenic markers [243]. Adiponectin injection in CIA mice resulted in ear-
lier arthritis onset, accelerated joint damage progression, severe synovial hyperplasia, bone
erosion, and osteoporosis. This was due to adiponectin-dependent Th17 cell response en-
hancement and upregulation of the RANKL/OPG ratio [244]. Adiponectin has been shown
to promote inflammation in RA by stimulating the production of pro-inflammatory factors
such as IL-6, IL-8, and prostaglandin E2 (PGE2 ) [245]. When exposed to adiponectin, FLS
derived from RA patients produce increased levels of the above-mentioned factors [245].
Skalska et al. [246] examined how adiponectin and leptin affect the immune-modulating
function of adipose mesenchymal stem cells (ASCs) from the infrapatellar fat pads of RA
patients. Adipose mesenchymal stem cells were exposed to leptin, LMW, and HMW/MMW
adiponectin isoforms. Unlike LMW adiponectin and leptin, HMW/MMW adiponectin sig-
nificantly boosted the secretion of transforming growth factor β (TGF-β), IL-6, interleukin
1 receptor antagonist (IL-1Ra), PGE2 , IL-8, and VEGF [246].
Adiponectin has also been linked to the dysregulation of joint tissue remodelling
processes in RA. Adiponectin is involved in neovascularisation, a hallmark of RA, and
induces the expression of VEGF in FLS and osteoblasts [247]. It also stimulates the ex-
pression of endocan, an endothelial dysfunction biochemical marker secreted by vascular
endothelial cells. Endocan levels are increased in RA synovial tissues, and adiponectin
stimulates its expression in RA FLS [247,248]. Adiponectin-stimulated FLS of RA patients
have increased levels of VEGF and MMPs [249,250], which play crucial roles in angio-
genesis, ECM degradation, and tissue remodelling. This upregulation by adiponectin
suggests a potential mechanism by which it contributes to the destructive processes in
RA joints [73]. Huang et al. [243] conducted a study to investigate the role of adiponectin
in angiogenesis in RA. They found that adiponectin increases the expression of VEGF in
a dose- and time-dependent manner, which stimulates the formation and migration of
endothelial progenitor cells (EPCs). These angiogenic activities induced by adiponectin
were facilitated by MEK/ERK signalling. In vivo experiments confirmed that adiponectin
downregulates microRNA-106a-5p (miR-106a-5p) [243].
Furthermore, adiponectin impairs osteoblast mineralisation capacity and enhances
osteoclast bone-resorptive activity [251]. It promotes the expression of MMP-9 and tartrate-
resistant acid phosphatase (TRAP) while increasing IL-8 secretion in osteoblasts. Addi-
tionally, adiponectin inhibits osterix expression in RA-induced human bone tissue and
induces osteoprotegerin mRNA expression, leading to impaired bone formation [251]. Qian
et al. [252] demonstrated that adiponectin promotes osteopontin production, which recruits
osteoclasts to the bone surface and initiates bone erosion.
These observations diverge from previous findings in healthy cells [253,254], sug-
gesting that the chronic inflammatory environment in RA alters the typical physiological
response to adiponectin [255], shifting from anti-osteoclastogenic to pathologically pro-
resorptive. As a result, adiponectin contributes to bone damage in RA by directly inhibiting
osteoblast differentiation and promoting osteoclastogenesis, leading to increased bone
resorption [255].
Specific antibodies against adiponectin isoforms were designed to specifically bind
to MMW and HMW adiponectin. This targeted approach resulted in a reduction of IL-6
and IL-8 induction in osteoblasts that had been stimulated by these isoforms [256]. Fur-
thermore, Lee et al. demonstrated that antibodies targeting both MMW/HMW and MMW
isoforms significantly improved CIA in mice, suggesting that both adiponectin isoforms
may contribute to the progression of RA [256].
Another study [257] revealed that while T follicular helper cells (Tfh) did not directly
respond to adiponectin, adiponectin indirectly affected these cells by activating them
through FLS stimulation, mediated primarily by IL-6. In support of these findings, Liu et al.
Biomedicines 2023, 11, 2998 17 of 48

demonstrated that intra-articular administration of adiponectin led to increased synovial

inflammation and a higher frequency of Tfh cells in mouse CIA [257].
Numerous studies have demonstrated elevated adiponectin levels in the serum and SF
of RA patients when compared with healthy controls or individuals with OA [200,202,219,
258–268] (Table 2). A meta-analysis encompassing 11 studies, including a cohort of 813 RA
patients and 669 healthy controls, showed a significant elevation in circulating adiponectin
levels among RA patients compared to the control groups [83]. A 29-year follow-up study
of subjects with obesity found that those with high serum adiponectin levels at baseline
were more likely to develop RA [269]. Furthermore, Tan et al. [270] conducted a study
that revealed abundant expression of adiponectin and its receptors, namely AdipoR1 and
AdipoR2, in the synovial membrane of RA patients, particularly within FLS.

Table 2. Association of adiponectin and rheumatoid arthritis in humans.

Reference Subjects Results/Outcomes

Serum adiponectin levels were significantly greater in RA patients
20 RA patients, 21 OA patients than in healthy controls and comparable with OA patients.
Senolt et al. (2006) [258]
23 healthy controls SF adiponectin was significantly greater in RA than in OA
patients and healthy controls.
Serum adiponectin levels in RA patients were significantly
31 RA patients greater than in controls.
Otero et al. (2006) [200]
18 controls without RA A positive correlation was observed between serum adiponectin
and CRP levels.
114 RA patients, 35 OA
RA patients had greater plasma adiponectin concentration than
Laurberg et al. (2009) [263] patients
healthy controls but lower plasma adiponectin than OA patients.
45 healthy controls
RA severity was assessed by examining joint destruction on
radiographs. Serum adiponectin levels were significantly greater
90 RA patients
Ebina et al. (2009) [265] in severe RA patients when compared to mild and control groups,
42 controls without RA
suggesting increased joint destruction is linked to
hyperadiponectinaemia in RA patients.
58 RA patients Serum adiponectin levels were significantly greater in all RA
Popa et al. (2009) [264]
58 controls without RA patients than in controls.
167 RA patients Serum adiponectin levels were significantly greater in all RA
Rho et al. (2010) [202]
91 controls without RA patients than in controls.
Serum adiponectin levels in RA patients were significantly grater
56RA patients than in controls.
Ozgen et al. (2010) [262]
29 controls without RA A positive correlation was observed between serum adiponectin
and DAS28.
The serum levels of adiponectin were significantly greater in RA
patients compared to controls, and RA patients with active
disease had significantly greater adiponectin levels than those
70 RA patients
Alkady et al. (2011) [260] in remission.
30 controls without RA
Serum and SF adiponectin levels positively correlated with the
duration of disease, ESR, CRP, and DAS28 in RA patients with
active disease.
Klein-Wieringa et al. A positive correlation existed between serum levels of
253 RA patients
(2011) [271] adiponectin and radiographic progression of RA over 4 years.
A positive correlation existed between serum adiponectin levels
Giles et al. (2011) [272] 152 RA patients
and erosive joint destruction.
56 RA patients Serum adiponectin was significantly greater in RA patients than
Ozgen et al. (2010) [262]
29 controls without RA in healthy controls.
Biomedicines 2023, 11, 2998 18 of 48

Table 2. Cont.

Reference Subjects Results/Outcomes

Female, but not male, RA patients had significantly greater serum
141 RA patients adiponectin concentrations than controls.
Yoshino et al. (2011) [219]
146 controls without RA Serum adiponectin levels were negatively associated with
CRP levels.
There was a significant correlation between serum adiponectin
Kang et al. (2013) [273] 192 RA patients
levels and ESR.
A positive association was observed between serum adiponectin
Meyer et al. (2013) [274] 632 RA patients
levels and early radiographic RA progression.
Serum adiponectin levels were significantly greater in RA
70 RA patients patients than in controls.
Toussirot et al. (2013) [275]
51 controls without RA In RA patients, HMW/total adiponectin correlated with
the DAS28.
No correlation existed between serum adiponectin and DAS28.
A negative correlation existed between serum adiponectin
Bustos Rivera-Bahena et al.
121 RA patients and TNFα.
(2015) [223]
A positive correlation existed between serum adiponectin
and IL-11β.
Serum levels of adiponectin were significantly greater in RA
Chennareddy et al. 43 RA patients patients when compared to the control group.
(2016) [268] 25 controls without RA There was no correlation with an erosive and non-erosive disease,
disease duration, BMI, waist–hip ratio, and DAS28.
Serum adiponectin levels were greater in all RA patients than
90 RA patients in controls.
Khajoei et al. (2019) [261]
30 controls without RA There was a positive correlation between serum adiponectin
levels and DAS28 and ESR.
3693 obese subjects followed High serum adiponectin levels at baseline were a significant risk
Zhang et al. (2020) [269]
for up to 29 years. factor for RA in the cohort of subjects with obesity.
Both total and HMW adiponectin were positively associated with
Vasileiadis et al. (2021) [232] 70 RA patients
DAS28 and CRP in RA patients.
Serum adiponectin levels were strongly associated with
Baker et al. (2022) [276] 2583 RA patients radiographic damage, seropositivity, longer disease duration, and
circulating inflammatory cytokines.
RA = rheumatoid arthritis; OA = osteoarthritis; CRP = C-reactive protein; TNFα = tumour necrosis factor-α;
ESR = erythrocyte sedimentation rate; DAS28 = Disease Activity Score 28; BMI = body mass index.

Several investigations [200,260–262,265,272,275,277,278] have found a positive correla-

tion between adiponectin serum levels and disease activity or radiographic progression.
Nevertheless, this association is not universally acknowledged, as other studies have pro-
duced contradictory findings [202,219,223,258,268,279]. Baker et al. [276] recently found
that adiponectin levels were strongly associated with radiographic damage, seropositivity,
longer disease duration, prednisone use, and circulating inflammatory cytokines in people
with rheumatoid arthritis. Nevertheless, they did not find a significant association between
adiponectin levels and DAS28 (Table 2). However, it has been postulated that adiponectin
holds promise as a valuable therapeutic biomarker to monitor the severity, progression,
and treatment outcomes of RA patients [261].

2.3. Visfatin
Visfatin is a multifunctional adipokine, also known as nicotinamide phosphoribo-
syltransferase (NAMPT). It is predominantly synthesised in large quantities in visceral
adipose tissue but is also expressed in numerous other organs and tissues, including the
bone marrow, liver, musculature, heart, placenta, lungs, and kidneys [280,281]. Its role
in inflammation and immune modulation has generated considerable interest. Visfatin,
Biomedicines 2023, 11, 2998 19 of 48

initially identified as an immune-modulating cytokine, has been shown to influence the

production of B cells, which are involved in the humoral immune response, and activate T
cells, which play a crucial role in the cell-mediated immune response [280–282]. Visfatin’s
immune-modulating properties have been elucidated, shedding light on its function in
stimulating the secretion of MCP-1, a chemokine that facilitates the recruitment of immune
cells to inflamed tissues. In addition, visfatin increases the expression of MMPs, enzymes
involved in tissue remodelling [283,284]. Remarkably, visfatin activates key inflammatory
signalling pathways, such as nuclear factor kappa B (NF-κB), MAPK, and PI3K, thereby
amplifying the inflammatory response [281,283,284]. When visfatin concentrations are
increased, several pro-inflammatory mediators, including IL-1β, IL-1Ra, IL-6, IL-8, and
TNFα, are expressed at elevated levels [280,281].
Studies in humans and experimental animal models suggest that visfatin may play a
significant role in the development of RA [166,200,202,260,285–291]. In studies employing
experimental animal models, elevated visfatin levels were associated with RA develop-
ment [289–291]. Additionally, a pro-inflammatory cytokine, IL-6, augmented the increase
in visfatin [289]. In a murine model of RA, visfatin expression in immune cells was linked
to the production of IL-6, the infiltration of immune cells, the proliferation of Th17 cells,
and the presence of autoantibodies associated with RA [292]. Experimental studies utilis-
ing visfatin blockers have shown promising results in attenuating pathological processes
associated with RA [291,292]. Notably, visfatin deficiency slowed the progression of RA, as
evidenced by reduced bone degradation and inflammation [292,293].
Visfatin expression has been detected in various cell types in the synovial tissue of RA
patients, including adipocytes and endothelial cells, with the highest expression observed
in FLS [289,294,295]. Visfatin can induce the activation of FLS, causing the release of pro-
inflammatory cytokines and catabolic proteins, which can lead to joint destruction [294,295].
Furthermore, visfatin was found to stimulate its own expression in FLS [294]. Studies by
Hasell et al. [296]. have demonstrated that visfatin plays a role in facilitating adhesion of
FLS to the endothelium and contributes to the early stages of the disease process within the
context of the adhesion cascade.
Visfatin is involved in matrix production during the differentiation of mesenchymal
stem cells (MSCs) and decreases collagen type I expression, highlighting its significance in
bone pathophysiology [297]. Gosset et al. [298] demonstrated that visfatin triggered the
release of PGE2 and the expression of catabolic enzymes in human chondrocytes, indicating
a potential role for visfatin in cartilage degradation. Visfatin fosters osteogenesis by enhanc-
ing runt-related transcription protein 2 (Runx2) expression. Inhibition of visfatin in mouse
bone marrow-derived MSCs (BM-MSCs) reduces osteoblastogenesis and hinders osteoblast
differentiation markers, alkaline phosphatase activity, and matrix mineralization [299].
It was demonstrated that visfatin could impede RANKL-induced osteoclast differentiation
by disrupting survival-related signalling pathways [300].
It was demonstrated that visfatin levels are greater in RA patients than in healthy
individuals [166,200,202,260,285–288]. A meta-analysis of 11 studies found that circulating
visfatin levels were significantly greater in RA patients than in healthy controls [83]. Addi-
tionally, there was a positive correlation between visfatin levels and anti-CCP antibodies
and the progression of RA [166,221,271,294]. Some studies have also found a positive
correlation between visfatin levels and disease activity [166,221,260,294]. Rho et al. [202]
demonstrated a positive association between visfatin levels and radiologically detectable
joint damage in RA patients after adjusting for confounding factors (Table 3).
Biomedicines 2023, 11, 2998 20 of 48

Table 3. Association of visfatin and rheumatoid arthritis in humans.

Reference Subjects Results/Outcomes

Serum visfatin levels in RA patients were significantly greater
31 RA patients than in controls.
Otero et al. (2006) [200]
18 controls without RA There was a positive correlation between serum visfatin and
CRP levels.
22 RA patients Serum visfatin levels in RA patients were significantly greater
Matsui et al. (2008) [286]
17 controls without RA than in controls.
A positive correlation existed between visfatin serum levels and
167 RA patients
Rho et al. (2010) [202] TNFα, IL-6, CRP, neutrophil count, MHAQ score, and
91 controls without RA
Larsen score.
Serum levels of visfatin were significantly greater in RA patients
than in controls, and RA patients with active disease had
70 RA patients significantly greater visfatin levels than those in remission.
Alkady et al. (2011) [260]
30 controls without RA Serum and SF visfatin levels positively correlated with the
duration of the disease, ESR, CRP, and DAS28 in RA patients with
active disease.
Klein-Wieringa et al. A positive correlation existed between visfatin serum levels and
253 RA patients
(2011) [271] the radiographic progression of RA for 4 years.
26 RA patients Serum visfatin levels in RA patients were significantly greater
Ozgen et al. (2011) [288]
29 controls without RA than in controls.
No association between serum visfatin level and radiographic
Meyer et al. (2013) [274] 632 RA patients
disease progression was observed.
There was a significant positive correlation between serum
visfatin and ESR, CRP, IL-6, TNFα, DAS-28, and VAS pain score
60 RA patients
Khalifa et al. (2013) [301] in RA patients.
20 controls without RA
No correlation existed between serum visfatin and age of RA
patients, disease duration, or BMI.
Serum visfatin levels in RA patients were significantly greater
40 RA patients
El-Hini et al. (2013) [287] than in controls. A positive correlation was observed between
40 controls without RA
serum visfatin and DAS28.
eRA patients had elevated serum visfatin levels compared to
healthy controls, which decreased after three months of treatment.
40 eRA patients, 30 controls
Sglunda et al. (2014) [166] Circulating visfatin and visfatin level changes correlated with
without RA
disease activity and improved over time, with a decrease in
visfatin predicting improvement in DAS28.
54 RA patients (29 with and 25 Serum visfatin levels were greater in patients with radiographic
Mirfeizi et al. (2014) [221]
without erosion) joint damage and dependent on the duration of the disease.
Serum visfatin levels in RA patients were significantly greater
Mohammed Ali et al. 60 RA patients 30 controls
than in controls. There was no correlation between serum visfatin
(2020) [302] without RA
levels and the DAS28.
RA = rheumatoid arthritis; eRA = early RA; CRP = C-reactive protein; TNFα = tumour necrosis factor-α;
IL-6 = Interleukin-6; ESR = erythrocyte sedimentation rate; DAS28 = Disease Activity Score 28; SF = synovial fluid.

Additionally, PBMCs and peripheral blood granulocytes (PBGs) from RA patients

had greater levels of visfatin expression when compared to healthy controls [286]. Visfatin
levels were also greater in the synovium of RA patients when compared to healthy controls
and OA patients [289]. Additionally, elevated visfatin levels in RA synovial joints positively
correlated with inflammation and clinical disease activity, further supporting the role of
visfatin in joint alterations associated with RA [294].
In their comprehensive review, Franco-Trepat et al. [303] provided compelling evi-
dence which showed that visfatin plays a crucial role in RA inflammatory and catabolic
processes. The authors proposed the existence of a positive feedback loop between visfatin
expression and various inflammatory factors, potentially contributing to the persistence of
Biomedicines 2023, 11, 2998 21 of 48

inflammation in RA [303]. Several authors have acknowledged the association between

visfatin and RA activity and progression, underscoring its potential as a promising thera-
peutic target [80,300,303–306]. Moreover, this association has sparked interest in exploring
visfatin’s role as a biomarker and its potential as a predictor of response to biologic treat-
ments [285,287,288,302,303,307].

2.4. Resistin
Resistin is a cysteine-rich peptide hormone encoded by the RETN gene, which belongs
to a family of secreted proteins known as resistin-like molecules (RELMs) or found in
inflammatory zone (FIZZ) proteins and is secreted by adipose tissue and other cells, such
as mononuclear leukocytes and macrophages [308]. Resistin has been proposed to link
obesity, insulin resistance, and diabetes in rodents, as it antagonises insulin action and
impairs glucose homeostasis [169,308].
In addition to its metabolic effects, resistin has been implicated in various inflammatory
and cardiovascular diseases. Resistin may contribute to the pathogenesis of these diseases
by modulating the immune response and inducing various pro-inflammatory cytokines.
Resistin may also affect vascular function by inhibiting endothelial nitric oxide synthase
(eNOS) activity, which promotes endothelial dysfunction, thrombosis, angiogenesis and
smooth muscle cell proliferation [308–310]. Moreover, resistin has been implicated in
the pathogenesis of autoimmune inflammatory diseases, including RA. In recent years,
researchers have explored the possible involvement of resistin in RA pathogenesis and its
potential as a biomarker and therapeutic target.
The administration of resistin to human articular chondrocytes resulted in the upregula-
tion of several cytokines and chemokines, including TNFα, IL-6, and IL-12 [311]. Additionally,
resistin treatment increased the expression of various catabolic enzymes and markers associ-
ated with cartilage degradation, such as MMP-1, MMP-2, and ADAMTS-4 [311]. Bokarewa
et al. [312] demonstrated that intra-articular injection of recombinant resistin in healthy mice
induced a joint inflammation similar to human arthritis [312]. They also showed that in
response to extracellular resistin, both human PBMC and synovial leukocytes produce various
pro-inflammatory cytokines, such as TNFα, IL-1β and IL-6. Remarkably, resistin stimulates
its own production in human PBMC, establishing a positive feedback loop.
Additionally, when exposed to TNFα but not IL-1β or IL-6, PBMCs demonstrate
an induced expression of resistin. The study provided evidence indicating that resistin,
expressed in the synovial tissue of individuals with RA, plays a role in the pathogenesis of
the disease by enhancing FLS chemokine production [312,313].
In a recent study [314], researchers employed the AIA-mouse model to investigate
the effects of intra-arterial resistin administration on PVAT function and showed that
resistin administration led to PVAT dysfunction. These findings are particularly intriguing,
considering that PVAT is known to primarily release pro-inflammatory adipokines under
pathological conditions, including resistin [72]. These observations suggest that resistin
might play a role in a pathological positive feedback loop, whereby PVAT dysfunction leads
to increased resistin production, further impairing PVAT function. These findings have
important implications for our understanding of how PVAT is involved in the development
of CVD in RA.
Some studies have demonstrated that resistin levels are elevated in the serum and SF
of RA patients when compared to healthy subjects and OA patients [165,200,202,206,216,
312,315–319]. However, some studies [219] found no significant difference in serum resistin
levels between RA patients and healthy individuals [219,260] (Table 4). The expression
of resistin has been documented by Šenolt et al. [320] in various cell types present in the
synovial tissue, including FLS, as well as in distinct inflammatory cell types observed in
the synovium of RA patients, namely macrophages, B lymphocytes, and plasma cells [320].
Several researchers have documented positive correlations between serum resistin levels
and markers of inflammation, such as ESR and CRP, as well as clinical disease activity as
measured by DAS28 in RA patients [206,219,223,228,315,318,320].
Biomedicines 2023, 11, 2998 22 of 48

Table 4. Association of resistin and rheumatoid arthritis in humans.

Reference Subjects Results/Outcomes

Serum resistin levels in RA patients were significantly greater
31 RA patients
Otero et al. (2006) [200] than in controls. There was no correlation between serum resistin
18 controls without RA
and CRP level.
Serum resistin levels in RA patients were significantly greater
42 RA patients
Migita et al. (2006) [316] than in controls. Serum resistin levels were correlated with RA
38 controls without RA
disease activity markers, CRP, ESR, and TNFα levels.
Serum resistin levels were not significantly different between
Forsblad d’Elia et al. 90 RA patients patients and healthy controls. Serum resistin levels were
(2008) [321] 30 controls without RA correlated with IL-1Ra, CRP, TNFα, ICTP, glucocorticosteroids,
Larsen score, and inversely with BMD, hip, and TLM.
167 RA patients Serum resistin levels were significantly greater in all RA patients
Rho et al. (2009) [202]
91 controls without RA than in the control group.
52 RA patients Plasma resistin levels in RA patients were significantly greater
Canoruç et al. (2009) [216]
52 controls without RA than in controls.
Serum and SF resistin levels in RA patients were significantly
greater than in controls and in active RA greater than in
non-active patients.
30 RA patients
Kassem et al. (2010) [315] A significant correlation existed between serum resistin levels and
15 controls without RA
CRP, ESR, RF, and disease activity.
A significant correlation existed between SF resistin levels and
CRP, ESR, RF, and synovial leukocytic count.
Serum resistin levels were not significantly different between
141 RA patients patients and healthy controls.
Yoshino et al. (2011) [219]
146 controls without RA A positive correlation was observed between serum resistin and
CRP levels.
70 RA patients No significant difference in serum resistin levels was observed
Alkady et al. (2011) [260]
30 controls without RA between RA patients and controls.
141 RA patients A positive correlation was observed between serum resistin and
Yoshino et al. (2011) [219]
146 controls without RA CRP levels.
Resistin levels were greater in serum and SF of RA patients when
compared to OA patients.
25 RA patients There was a correlation between serum resistin levels, Larsen
Fadda et al. (2013) [317]
25 OA patients score, and total leukocyte count.
A correlation existed between SF resistin levels and RF, ACPA,
and Larsen score.
A significant correlation existed between serum resistin levels,
Kang et al. (2013) [273] 192 RA patients
ESR, CRP, and disease duration.
30 RA patients Serum resistin levels in RA patients were significantly greater
Hammad et al. (2014) [319]
30 controls without RA than in controls.
Bustos Rivera-Bahena et al. A positive correlation was observed between resistin serum levels
121 RA patients
(2015) [223] and the DAS28.
High resistin levels were associated with active inflammatory
Vuolteenaho et al. (2022) [322] 99 RA patients disease and predicted rapid radiological progression during
5-year follow-up.
Serum resistin levels in RA patients were significantly greater
Arias-de la Rosa et al. (2022) 150 RA patients than in controls.
[206] 50 controls without RA A positive correlation was observed between resistin serum levels
and the DAS28.
RA = rheumatoid arthritis; OA = osteoarthritis; CRP = C-reactive protein; TNFα = tumour necrosis factor-α;
ESR = erythrocyte sedimentation rate; DAS28 = Disease Activity Score 28; ICTP = carboxyterminal cross-linked
telopeptide of type I collagen; TLM = total lean mass, RF = rheumatoid factor.
Biomedicines 2023, 11, 2998 23 of 48

Bokarewa et al. [312] found that the resistin levels in SF of RA patients were signifi-
cantly greater than in those with OA or other primarily non-inflammatory joint diseases.
However, they observed lower resistin concentrations in the serum of RA patients, com-
pared with the matched SF samples, indicating a potential increase in local production or
selective accumulation of this adipokine at the site of inflammation [312]. In a meta-analysis
encompassing eight studies involving 620 patients with RA and 460 healthy controls, it was
found that serum resistin levels in RA patients were significantly elevated when compared
to those in the control group [323]. Anti-TNFα therapy reduced serum resistin levels in
RA patients, indicating a strong correlation with inflammatory markers [324,325]. In the
early phases of active RA, it has been proposed that measuring resistin concentration could
be a valuable biomarker for identifying individuals at high risk of developing erosive
disease [322].

2.5. Other Adipokines

2.5.1. Vaspin
Vaspin is classified as an adipokine belonging to the serine protease inhibitor family.
Its expression has been observed in both visceral and subcutaneous adipose tissue in adult
humans [326]. Its regulation may vary depending on the specific adipose tissue depot and
is associated with obesity, glucose metabolism, and insulin resistance. The expression of
vaspin is notably high in the liver and skin, while it is moderately expressed in the brain,
heart, and spleen. The mRNA expression of vaspin is elevated in individuals who suffer
from obesity and T2D [326].
Furthermore, a positive correlation exists between circulating vaspin and vaspin
mRNA expression levels in adipose tissue. Several studies have postulated that vaspin
can enhance ATK signalling and inhibit NF-κB signalling in adipocytes, increasing in-
sulin sensitivity in both adipocytes and hepatocytes [326,327]. Additionally, vaspin has
been found to attenuate the pro-inflammatory cytokine response induced by IL-1β in
adipocytes [326,327].
In in vitro studies, human osteoblasts were protected from apoptosis, which may be
attributed to the activation of the MAPK/ERK signalling pathway [328]. In their research,
Kamio and colleagues [329] noted that vaspin inhibited RANKL-induced osteoclastogenesis.
Notably, vaspin demonstrated inhibitory effects on the expression of nuclear factor of
activated T cells c1 (NFATc1) induced by RANKL. Moreover, it inhibited the enhancement
of MMP-9 and cathepsin K induced by RANKL. The authors suggested that vaspin could
downregulate osteoclastogenesis by partially suppressing the transcription factor NFATc1.
A study by Wang et al. [330] revealed that vaspin has a protective effect against bone loss
induced by an HFD.
Furthermore, it showed that vaspin facilitated the osteogenic differentiation process
by activating the Smad2/3-Runx2 signalling pathway. This observation seems contradic-
tory to previous findings by Liu et al. [331], who observed that vaspin inhibits osteogenic
differentiation in the pre-osteoblast cell line MC3T3-E1 and proposed that this inhibition
is mediated through a regulatory loop involving the PI3K-Akt signalling pathway and
miR-34c. These contradictory results could be due to several factors, including differ-
ences in the experimental models used (pre-osteoblast cell line MC3T3-E1 vs. primary
rat osteoblasts). Additionally, Bao et al. demonstrated that vaspin prevented leptin- and
IL-1β- induced inflammation and catabolism by inhibiting the activation of NF-κB in rat
chondrocytes [332,333].
The complete evaluation of vaspin’s potential role in rheumatic conditions such as
RA is still incomplete. Multiple sources [225,262,334,335] indicate that individuals with RA
have elevated serum vaspin levels when compared to healthy subjects (Table 5). Vaspin
levels in SF were significantly greater in patients with RA than in OA patients [334].
Furthermore, a correlation was observed between vaspin levels and DAS28 in the RA
cohort. However, the study found no correlation between serum vaspin levels and serum
CRP levels or leukocyte count in the SF of RA patients [334].
Biomedicines 2023, 11, 2998 24 of 48

Table 5. Association of other selected adipokines and adipomyokines and rheumatoid arthritis
in humans.

Reference Subjects Results/Outcomes

56 RA patients Serum vaspin levels were significantly greater in RA patients than
Ozgen et al. (2010) [262]
29 controls without RA in healthy controls.
Serum levels of chemerin and vaspin were greater, while those of
apelin and omentin were lower, in RA patients than in
150 RA patients
Wahba et al. (2021) [335] healthy controls.
150 controls without RA
A significant positive correlation existed between vaspin serum
levels and BMI, DAS28, ESR, CRP, RF, and anti-CCP antibodies.
SF vaspin levels were significantly greater in RA patients than in
OA patients.
A positive correlation existed between vaspin SF levels
Senolt et al. (2010) [334] 33 RA patients, 33 OA patients
and DAS28.
SF omentin levels were significantly lower in RA patients than in
OA patients.
Plasma chemerin levels in RA patients were significantly greater
71 RA patients than in controls.
Ha et al. (2013) [336]
42 controls without RA There was a positive correlation between plasma chemerin levels
and DAS28.
Serum PGRN levels in RA patients were significantly greater than
56 RA patients, 31 OA patients in controls.
Yamamoto et al. (2014) [337]
417 controls without RA SF PGRN levels were significantly greater in RA patients than in
OA patients.
Serum PGRN levels correlated with DAS28 and HAQ scores in
47 RA patients, 42 OA patients RA patients.
Cerezo et al. (2015) [338]
41 controls without RA The SF PGRN levels were significantly greater in RA than in
healthy controls and OA patients.
Serum PGRN levels in RA patients were significantly greater than
80 RA patients, 60 controls in controls.
Chen et al. (2016) [339]
without RA A significant positive correlation existed between serum PGRN
and DAS28, ESR, and CRP in RA patients.
Serum PGRN levels in RA patients were significantly greater than
52 RA patients, 19 controls in controls.
Fouad et al. (2019) [340]
without RA A significant positive correlation existed between serum PGRN,
DAS28, and ESR in RA patients.
RA patients with severe disease had greater serum nesfatin-1
110 RA patients, 60 controls
Kvlividze et al. (2019) [341] levels, positively correlated with greater CRP and ESR
without RA
concentrations.
Serum irisin levels were significantly lower in RA patients than
in controls.
Serum irisin levels in RA-poor sleepers were significantly lower
58 RA patients, 30 controls than in RA-good sleepers.
Gamal et al. (2020) [342]
without RA Serum irisin levels in RA patients were associated with total
Pittsburgh Sleep Quality Index scores.
Irisin serum levels of RA patients were negatively associated with
disease duration, morning stiffness duration, and DAS28.
Gonzalez-Ponce et al. A positive correlation was found between chemerin and DAS 28,
210 RA patients
(2021) [343] CRP, and swollen joints counts.
Vazquez-Villegas et al. Elevated chemerin levels were associated with functional
82 RA patients
(2021) [344] disability in RA.
Biomedicines 2023, 11, 2998 25 of 48

Table 5. Cont.

Reference Subjects Results/Outcomes

Nesfatin-1 levels in the synovium were significantly greater in RA
40 RA patients, 15 controls patients than in controls.
Zhang et al. (2021) [345]
without RA Nesfatin-1 levels positively correlated with IL-1β and TNFα
levels in the synovium of patients with RA.
MSTN serum levels were significantly greater in the RA group
than in the controls.
Murillo-Saich et al. 84 RA patients, 127 controls Greater MSTN levels correlated with low skeletal muscle
(2021) [346] without RA mass index.
A positive correlation existed between MSTN serum levels and
DAS28, CRP and ESR.
In a prospective cohort of consecutive RA patients with a
one-year follow-up, it was found that RA patients had greater
serum MSTN levels at baseline when compared to healthy
controls. Elevated serum MSTN and myopenia are risk factors for
radiographic progression in RA.
344 RA patients, 118 controls
Lin et al. (2022) [347] RA patients with elevated MSTN overlapping myopenia had the
without RA
highest levels of DAS28, SDAI, CDAI, and HAQ-DI at 3, 6, and
12 months, with the lowest proportion of CDAI remission at
3 months, 9 months, and 12 months.
They also had the highest proportion of physical dysfunction at 3,
9, and 12 months.
MSTN serum levels were significantly greater in the RA group
Gonzalez-Ponce et al. 161 RA patients, 72 controls than in the controls.
(2022) [348] without RA Elevated MSTN levels in RA patients increased the risk
of cachexia.
Serum irisin levels were significantly lower in RA patients than
60 RA patients, 30 controls in controls.
Soliman et al. (2022) [349]
without RA Serum irisin levels in RA patients negatively correlated with
DAS28, CRP, ESR, and HAQ-DI.
Serum irisin levels were significantly lower in RA patients than
Gamez-Nava et al. 148 RA patients, 97 controls in controls.
(2022) [350] without RA Low serum irisin levels were associated with the presence of
vertebral fractures in female patients with RA.
Serum omentin and vaspin levels in RA patients were
Arias-de la Rosa et al. 150 RA patients significantly higher than in controls.
(2022) [206] 50 controls without RA A positive correlation was observed between omentin serum
levels and the DAS28.
RA = rheumatoid arthritis; OA = osteoarthritis; CRP = C-reactive protein; TNFα = tumour necrosis factor-α;
IL-6 = Interleukin-6; ESR = erythrocyte sedimentation rate; DAS28 = Disease Activity Score 28; PGRN = pro-
granulin; MSTN = myostatin; CDAI = clinical disease activity index; SDAI = simplified disease activity index;
HAQ-DI = health assessment questionnaire–disability index; SF = synovial fluid.

Maijer et al. [351] have suggested that serum vaspin levels may be a potential biomarker
for predicting the development of RA in autoantibody-positive individuals.

2.5.2. Chemerin
Chemerin, encoded by the Rarres2 gene, is a versatile protein with diverse functions in
inflammation, adipogenesis, angiogenesis, and energy metabolism. As a small chemotactic
protein, chemerin is secreted as an inactive prochemerin and requires proteolytic activation
by serine proteases to unleash its biological activity. It binds to three G protein-coupled
receptors: chemokine-like receptor 1 (CMKLR1/chemerin1), G protein-coupled receptor 1
(GPR1/chemerin2), and CC-motif chemokine receptor-like 2 (CCRL2), found on a variety
of cells, including DCs, macrophages, and natural killer cells, where they regulate chemo-
taxis toward the site of inflammation and activation state. Predominantly expressed in
Biomedicines 2023, 11, 2998 26 of 48

adipocytes and immune cells, CMKLR1 is a key receptor for chemerin signalling [352,353].
In humans, chemerin levels positively correlate with BMI and obesity-related biomarkers.
It is highly expressed in WAT, liver, and lung, which suggests its involvement in energy
homeostasis and metabolic regulation. Chemerin acts through CMKLR1 to influence
adipogenesis, angiogenesis, and inflammation within adipose tissue. It is implicated in
metabolic disorders such as metabolic syndrome, insulin resistance, and obesity, acting as
a pro-inflammatory adipokine with complex endocrine, paracrine, and autocrine effects.
However, its role as a pro- or anti-inflammatory modulator remains unclear, as chemerin
can exhibit anti-inflammatory properties under specific conditions [352,353].
Chemerin stimulates FLS to produce metalloproteinases, especially MMP-3, which
results in cartilage degradation and joint degeneration [354]. Chemerin also exacerbates
inflammation in patients with RA by inducing the production of various pro-inflammatory
cytokines, such as IL-1β and IL-6 [354].
Additionally, greater chemerin concentrations cause increased MMP-2, MMP-3, MMP-13,
and IL-8 production in RA patients [355]. In addition, chemerin-stimulated chondrocytes
in RA patients can induce other molecules involved in cartilage degradation, such as
C-C motif ligand 2 (CCL2) [356]. Chemerin also facilitates the migration of immune cells
and FLS to the joints, accelerating cartilage degradation [354]. These results suggest that
chemerin plays a role in joint inflammation and cartilage destruction. Elevated chemerin
serum levels were observed in RA patients when compared to healthy controls [302,335].
Additionally, the chemerin concentration in SF of individuals with RA was significantly
increased, which is primarily due to the robust chemerin production by FLS [354,356].
Chemerin is also closely associated with the severity and activity of RA, making it a
useful biomarker [302,336,343] (Table 5). Furthermore, Vazquez-Villegas et al. [344] found
a correlation between elevated chemerin levels and functional disability in RA patients.

2.5.3. Omentin
Omentin-1 and omentin-2 are exclusively secreted by adipose tissue depots. In a study
by Yang et al. [357], the gene expression of these molecules was discovered in visceral
stromal vascular cells but not in adipocytes. Omentin-1 is the predominant isoform in
human plasma, and its expression is predominantly observed in omental adipose tissue
but not subcutaneous adipose tissue [358]. Omentin-1 has anti-inflammatory properties
and plays crucial functions in regulating glucose homeostasis, lipid metabolism, insulin
resistance, and the development of diabetes [359]. Omentin can enhance insulin signal
transduction by activating Akt/PKB, affecting adipose tissue distribution [357].
There is currently limited knowledge regarding the role of omentin in RA. Nonetheless,
some studies have suggested that omentin may be involved in the pathogenesis of RA.
Maijer et al. [351] found a positive correlation between serum omentin levels and CRP in
individuals with an increased risk of developing RA who tested positive for autoantibodies.
Arias-de la Rosa et al. [206] observed that serum omentin levels in RA patients were
significantly greater than in controls and a positive correlation between omentin serum
levels and the DAS28. Robinson et al. [360] found a correlation between omentin and
MMP-3 levels in patients with mild RA but not in those with severe RA. Wahba et al. [335]
observed that omentin serum levels were lower in RA patients than in healthy controls.
In addition, Senolt et al. [334] demonstrated that the SF levels of omentin in individuals
with chronic-inflammatory RA were significantly lower than those in individuals with OA
(Table 5).

2.5.4. Progranulin
Human progranulin (PGRN) is a 75–80 kDa glycoprotein composed of seven gran-
ulin/epithelin repeats. It is biologically active, with anti- and pro-inflammatory effects.
Originally described as an autocrine growth factor, PGRN stimulates chondrocyte differen-
tiation and proliferation and has been identified as an adipokine with anti-inflammatory
properties due to its competitive binding to TNFα receptors [361,362]. Several cells, includ-
Biomedicines 2023, 11, 2998 27 of 48

ing adipocytes, macrophages, and chondrocytes, secrete PGRN. Emerging evidence shows
that PGRN is protective in immune-mediated diseases, including RA [363].
Human progranulin is a potent stimulator of cartilage differentiation [361]. It enhances
cartilage chondrogenesis and repair by modulating BMP2 signalling and protects cartilage
from degradation and bone resorption by activating the ERK1/2 and JunB pathways
while inhibiting NF-κB and TNFR1 pathways. Additionally, PGRN suppresses TNFα
and ADAMTS-7/12, which are involved in cartilage degeneration in arthritis [361,364].
Moreover, PGRN regulates miR-138, which targets histone deacetylase 4 and affects NF-κB
levels in RA [365], attenuates the inhibitory effects of TNFα on osteoblast differentiation,
and prevents cartilage oligomeric matrix protein (COMP) degradation [365]. Treatment
with PGRN has been shown to prevent the loss of proteoglycans and to prevent the
expression of inflammatory biomarkers in human cartilage [366]. Other studies have shown
that PGRN can activate anabolic pathways and inhibit catabolic metabolism in chondrocytes
by binding to TNFR2 and blocking TNFR1 and also negatively modulates Wnt/catenin
signalling, reducing osteophyte formation and cartilage degeneration [367–370].
Recently, the potential role of PGRN as a biomarker and a therapeutic agent has been
suggested [368]. The complete PGRN protein exhibits anti-inflammatory characteristics;
however, it is not a viable therapeutic target due to its multifunctional nature in promoting
tumourigenesis and its susceptibility to proteolytic cleavage, resulting in the formation of
pro-inflammatory granulins [368]. In order to address these limitations, a novel protein
known as Atsttrin was engineered [368,371].
Tang et al. [371] investigated the role of PGRN as a modulator of TNFα/TNFR sig-
nalling and its therapeutic potential for RA. They showed that PGRN acts as an endogenous,
competitive TNFα antagonist by binding to TNFR and blocking its interaction with TNFα.
They also demonstrated that PGRN deficiency exacerbates arthritis inflammation in a
CIA model, while recombinant PGRN administration ameliorates it. Furthermore, they
compared the anti-inflammatory effects of PGRN and Atsttrin, a synthetic protein derived
from three PGRN fragments, which has enhanced TNFR affinity. They found that both
proteins reduced arthritis severity in various models, but Atsttrin was more potent than
PGRN in inhibiting inflammation [371].
Some studies have reported the clinical relevance of PGRN in RA. These studies
consistently show that RA patients have greater levels of PGRN in their serum than healthy
individuals, regardless of sex and age [337–339]. In RA patients, PGRN was associated with
disease activity [338–340] (Table 5), while the ratio of PGRN to TNFα closely correlated
with the progression of RA [337]. A study by Chen et al. [287] noted greater populations
of human B regulatory cells (Breg) in RA patients; however, Breg cell numbers did not
correlate with PGRN level, suggesting an independent alteration in RA [339]. Levels of
PGRN are significantly greater in the SF of RA patients than in OA patients [337,339],
with immunohistological analysis of synovial tissue from RA patients confirming this
upregulation of PGRN in inflammatory cells [338].

2.5.5. Lipocalin 2
Lipocalin-2 (LCN2), or neutrophil gelatinase-associated lipocalin (NGAL), is a glyco-
protein from adipose tissue that modulates inflammation and metabolism and has been
linked to obesity, hyperglycaemia, and insulin resistance [372]. In chondrocytes, LCN2 is
produced in response to IL-1β, leptin, adiponectin and LPS [373,374]. In these cells, it binds
to MMP-9 and prevents its auto-degradation [375,376], which may facilitate cartilage matrix
breakdown, as MMP-9 degrades cartilage components [374,375]. Moreover, LCN2 stimu-
lates synovial cell proliferation and inflammatory cell infiltration in RA synovium [376].
LCN2 has been proposed as a biomarker of cartilage degradation in arthritic diseases;
however, additional investigations are required to validate this hypothesis [377].
Biomedicines 2023, 11, 2998 28 of 48

2.5.6. Nesfatin-1
Nesfatin-1 is an anorexigenic molecule that plays a crucial role in the regulation of
energy homeostasis. It is secreted by the hypothalamus and other tissues, including SAT,
stomach, pancreas, and testes [378]. The expression of nesfatin-1 has also been observed in
chondrocytes of both human and mouse origin [379]. Xu et al. [380] evaluated the effects
of nesfatin-1 on acidosis-stimulated chondrocyte injury in vitro and in vivo, focusing on
the involvement of acid-sensing ion channel 1a (ASIC1a) and its mechanism of action in
RA. In vitro experiments showed that nesfatin-1 decreased cytotoxicity and intracellular
Ca2+ levels and attenuated oxidative stress, inflammation, and apoptosis in chondrocytes.
In vivo, the analysis revealed that nesfatin-1 ameliorated cartilage degradation and de-
creased ASIC1a expression in chondrocytes of rats with RA.
Chang et al. [381] analysed gene expression in synovial tissue samples from RA pa-
tients and CIA mice. Their findings revealed higher levels of nesfatin-1 and osteoclast
markers in these samples compared to those from normal synovium. Sequencing of RNA
revealed that nesfatin-1 increased Bone morphogenetic protein 5 (BMP5) expression in
FLS, while short hairpin RNA reduced BMP5 and osteoclast formation in CIA mice [381].
Patients with severe disease had greater serum nesfatin-1 levels, which positively correlated
with greater CRP and ESR concentrations [341]. Nesfatin-1 levels in the synovium were
significantly elevated in patients with RA when compared to the control group. Further-
more, a positive correlation was observed between nesfatin-1 levels in the synovium and
the presence of RF in patients with RA [345] (Table 5).

2.5.7. Apelin
Apelin, a protein found in numerous tissues, is a natural ligand for the apelin receptor
(APJ) which has anti-inflammatory properties and inhibits the NF-κB and ERK1/2 sig-
nalling pathways. In cases of obesity, both adipose tissue and plasma apelin levels are
elevated [169,382]. Evidence suggests that apelin might be involved in RA, as early-stage
RA patients have lower levels of this peptide than healthy individuals [383]. More recently,
Wahba et al. [335] demonstrated decreased apelin serum levels in RA patients (Table 5)
and revealed a negative correlation between apelin and NF-κB levels. Furthermore, the
same study revealed an inverse correlation between apelin levels and MMP-3 levels in RA
patients, indicating that decreased apelin promotes MMP-3 expression via NF-κB induced
transcription [335].

2.6. Adipomyokines
Numerous molecules are actively secreted by both skeletal muscle cells and adipocytes.
These molecules, known as adipomyokines, play a pivotal role in metabolic pathways and
are instrumental in facilitating muscle growth, regeneration, and intricate communication
among various tissues such as muscles, liver, WAT, BAT, brain, and bone [384].
Irisin and MSTN are among the best-characterised adipomyokines, exhibiting sig-
nificant interdependence in the context of adipose tissue muscle tissue crosstalk. This
intricate relationship is of considerable significance and can potentially contribute to RA
pathogenesis, with particular emphasis on SO.

2.6.1. Myostatin
Myostatin, alternatively referred to as growth differentiation factor 8, is a myokine
that has been thoroughly investigated due to its profound influence on muscle and adipose
tissue [385–387]. It is predominantly expressed in skeletal muscle and also in WAT, BAT,
and cardiac muscle [388–390]. Being a member of the transforming growth factor super-
family, MSTN exerts its effects through interaction with the ActRIIB receptor, leading to the
phosphorylation of the Smad2 and Smad3 proteins [391]. This phenomenon results in the
suppression of protein synthesis in skeletal muscle by inhibiting the IGF-1/Akt/mTOR
pathway [391]. Consequently, the activation of genes implicated in muscle protein degra-
dation is observed concomitantly with the inhibition of protein synthesis. Furthermore,
Biomedicines 2023, 11, 2998 29 of 48

MSTN plays a significant role in muscle atrophy via the FoxO1 signalling pathway while
also exerting an inhibitory effect on glucose uptake in skeletal muscle by downregulating
GLUT4 and AMPK activity [385–387,391].
In animal obesity models and obese humans, MSTN is upregulated [392,393]. Regular
physical activity decreases MSTN expression in the skeletal muscles of obese individu-
als [393,394]. Studies have demonstrated a positive association between MSTN levels and
intramuscular adipose tissue, suggesting a potential involvement of this myokine in the
development of myosteatosis [103]. Follistatin is a protein which binds to MSTN and
inhibits its function, promoting muscle hypertrophy. Exercise has been shown to increase
circulating levels of follistatin [395].
The pivotal role of MSTN in the development of RA is widely acknowledged in the sci-
entific literature [90,346,347,396–399], as it upregulates TNFα and IL-1β expression through
the PI3K-Akt signalling pathway in FLS, promoting muscle atrophy and osteoclast differ-
entiation [396]. Hu et al. [400] found that MSTN and IL-1β levels in synovial fluid from RA
patients were overexpressed and positively correlated, and MSTN dose-dependently regu-
lated IL-1β expression through the ERK, JNK, and AP-1 signal-transduction pathways. In a
mouse model of RA, it has been demonstrated that MSTN acts via the myostatin-CCL20-
CCR6 pathway to promote the migration of Th17 cells to inflamed joints. Interestingly,
IL-17A strongly regulates the expression of MSTN in FLS [398]. The authors hypothesised
that elevated MSTN levels contribute to the secretion of CCL20, which further facilitates
the infiltration by Th17 lymphocytes. As a result, the interaction between activated FLS and
Th17 cells, mediated by MSTN and IL-17A, establishes a negative inflammation feedback
loop. This maintains the continuous infiltration by Th17 cells, thereby contributing to the
persistence of chronic joint inflammation [398]. Expression of MSTN is elevated in the syn-
ovial tissues of RA patients and hTNFtg mice, an animal model of RA. Myostatin increases
RANKL-induced osteoclastogenesis in vitro by regulating NFATC1 via SMAD2 [399]. De-
ficiency of MSTN or its neutralisation reduces the severity of arthritis in hTNFtg mice,
primarily through a decrease in bone resorption. Likewise, in the K/BxN serum-transfer
arthritis model in rodents, MSTN ablation increases grip strength and decreases bone
erosion [399].
Greater plasma MSTN levels have been observed in RA patients when compared
to healthy controls, along with their association with disease activity and inflammatory
biomarkers [346–348] (Table 5). Elevated MSTN levels were shown to increase the risk of
rheumatoid cachexia [346,348] in RA patients. Lin et al. [347] found that elevated levels of
MSTN in the bloodstream were associated with cumulative joint injury in a cohort of RA
patients. This finding provided compelling evidence for the intricate relationship between
muscle and bone in the context of RA. Additionally, the researchers observed a synergistic
interaction between elevated serum MSTN levels and baseline loss of skeletal muscle in
RA patients [347], which could be used to predict the progression of radiographic joint
injury over one year. These findings emphasise the probable involvement of MSTN and
muscle–bone interactions in RA disease progression as prognostic factors [347].
Myostatin is a negative regulator of skeletal muscle mass growth and development [386,387]
and has been suggested as a possible biomarker for decreased muscle mass in RA patients.
However, data regarding the relationship between MSTN levels and muscle health in RA
have been inconsistent [89,346–348,397,401]. This discrepancy may be due to the observed
correlation between MSTN levels and RA disease activity [346]. Specifically, the increase
in MSTN may be partially due to the inflammation inherent in RA, independent of its
direct impact on muscle health [346]. Furthermore, it has been hypothesised that MSTN
could impede irisin biosynthesis, thereby promoting adipose tissue accumulation while
concurrently reducing muscle mass, contributing to the development of SO [386].

2.6.2. Irisin
Irisin is a peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-dependent
myokine that is released into the bloodstream by cleavage of the type III fibronectin do-
Biomedicines 2023, 11, 2998 30 of 48

main (FNDC5) protein-triggered muscle contraction. This release leads to browning and
regulation of thermogenesis in WAT [402,403]. Irisin, a myokine originally thought to
be exclusively produced by skeletal muscle, has recently been found to be released from
adipose tissue as well [404] and in smaller amounts from the liver, bone, testes, pancreas,
brain, spleen, heart, and stomach [405–407]. At first, interest in irisin was due to its ability
as a fat browning inducer and thermogenesis regulator [402,403]; however, further research
showed its multipotentiality and its influence on the nervous, cardiac, and musculoskeletal
systems. Moreover, its influence on the regulation of energy metabolism and its anti-
inflammatory and antioxidative actions have been widely described [408–411]. Irisin affects
target cells by interacting with membrane integrins αV/β5, responsible for cell-to-cell and
cell-to-ECM interactions, thus playing an important role in cell activation, proliferation,
adhesion, and migration [412].
Irisin has been shown to stimulate the differentiation and development of osteoblasts [409].
Osteoid formation increases osteoblasts while reducing osteoclasts, which is important in
bone formation [407,409]. Colaianni et al. [407] showed that irisin affects bone formation in
mice by inducing mRNA expression of early osteoblastic differentiation genes, including
marrow-activating transcription factor 4 (Atf4), runt-related transcription factor-2 (Runx2),
and Sp7 transcription factor (Sp7), which consequently launches a global osteogenesis
program. Work by Qiao et al. [413] indicated that irisin promotes osteoblast proliferation,
differentiation and mineralisation via p38 MAPK and ERK signalling pathways. Irisin
increases the strength of cortical bone and its resistance to bending and torsion by increas-
ing bone mass and improving bone density, length, thickness, periosteal perimeter, and
geometry [407,409,413]. However, the anabolic effect of irisin action is specific to long
cortical bones and not trabecular bones, where irisin action was not observed [407]. Irisin
has also been shown to strengthen the structural support that the subchondral bone pro-
vides to cartilage [409]. Irisin exerts an anti-apoptotic effect on osteocytes by increasing the
expression of Atf4 [414].
Furthermore, irisin stimulates chondrocyte proliferation, reducing the secretion of
inflammatory factors and MMP while increasing the expression of tissue inhibitor of
metalloproteinases (TIMP) in these cells [409]. Irisin also reduces the differentiation into
osteoblasts in human osteoarthritic chondrocytes (hOAC) collected from OA patients [415],
inhibits chondrocyte apoptosis, and increases the stability of the surrounding ECM [409].
The chondrogenic effects of irisin are mediated by the MAPK-NFκB pathway, including
inhibition of p38, AKT, and JNK phosphorylation, but not ERK [415]. In a mouse model of
OA, irisin exerted a chondroprotective effect by inhibiting inflammation-induced oxidative
stress, promoting its biogenesis, preventing mitochondrial fusion and mitophagy, and
regulating autophagy and apoptosis for survival [416].
In myotubes, irisin induces the expression of pro-myogenic genes, increases myogenic
differentiation, and promotes myoblast fusion [417,418]. The administration of exogenous
irisin improves regeneration, induces hypertrophy, and reduces protein degradation by
activating satellite cells and increasing protein synthesis in mice [418]. Irisin also has an
anti-atrophic effect on C2C12 myotubes treated with dexamethasone, a recognised inducer
of muscle atrophy, by inhibiting FoxO-dependent ubiquitin-proteasome overactivity [419].
In animal experiments, inhibiting MSTN caused an increase in irisin levels [420]. Irisin
has been previously associated with a reduction in adipose tissue mass and an enhancement
in insulin sensitivity [421,422].
Recent research utilising rats with experimental arthritis showed that irisin has thera-
peutic potential due to its anti-inflammatory and antioxidant actions [423]. Furthermore,
RA patients had substantially reduced irisin levels in their serum when compared to
healthy controls [342,349,350], and irisin levels were significantly inversely correlated with
disease activity and disability in RA patients [342,349] (Table 5). Low serum irisin levels
were also associated with the presence of vertebral fractures in RA-positive women [350].
Interestingly, poor sleep quality in RA patients may be linked to decreased serum irisin
Biomedicines 2023, 11, 2998 31 of 48

levels, suggesting a possible association between sleep impairment and irisin levels in
healthy controls [342].

3. Conclusions
Experimental and clinical evidence demonstrates the significance of adipokines and
adipomyokines such as irisin and MSTN in RA. These molecules can contribute to in-
flammation, immune dysregulation, joint destruction, and metabolic disturbances in this
disease. Emerging research highlights the intricate interaction between adipose tissue and
skeletal muscle, further implicating their role in RA.
Adipokines have shown promise as biomarkers in RA, providing valuable information
regarding disease activity, prognosis, and response to treatment. Several adipokines,
including adiponectin, leptin, resistin, and visfatin, have been investigated as potential
biomarkers for RA diagnosis and disease monitoring. Dysregulation of these adipokines in
serum or SF is correlated with disease severity, joint damage, and systemic manifestations in
RA patients. Furthermore, elevated levels of MSTN might function as valuable biomarkers
for the detection of individuals susceptible to the development of rheumatoid cachexia
and myopenia.
The identification of adipokines as potential therapeutic targets also provides new
opportunities for the treatment of RA. It may be possible to modulate the levels and func-
tions of pro-inflammatory adipokines while simultaneously enhancing the production
or effectiveness of anti-inflammatory adipokines. Focusing on MSTN could potentially
alleviate muscle wasting, enhance metabolic regulation, and regulate the inflammatory
environment within RA. Nonetheless, certain challenges need to be addressed to success-
fully translate adipokine-based therapies into clinical practice, such as comprehending
the intricate nature of the network formed by these molecules, accounting for patient het-
erogeneity, and developing techniques for targeted delivery into specific tissues. In order
to optimise combination therapies, it is essential to grasp how adipokines interact with
current treatments for RA. By incorporating adipokine profiling into clinical strategies,
early detection can be improved, treatment decisions can be better guided, and disease
activity in RA can be efficiently monitored.
In summary, adipokines and adipomyokines play a crucial role in the pathogenesis of
RA and have the potential as biomarkers for disease diagnosis, monitoring, and prognosis.
Further research on adipokines and adipomyokines will aid in the development of person-
alised and targeted therapeutic strategies, ultimately improving outcomes and patient care
in RA.

Author Contributions: Conceptualization, J.B. (Jan Bilski), J.B. (Joanna Bonior) and M.S.; writing—original
draft preparation, J.B. (Jan Bilski), M.S. and A.I.M.-B.; visualization, J.B. (Joanna Bonior) and A.S.-L.;
writing—review and editing, J.B. (Jan Bilski), J.B. (Joanna Bonior), M.S., A.I.M.-B., A.S.-L., K.L., K.Z.
and J.S. All authors have read and agreed to the published version of the manuscript.
Funding: This study received support from grant No. N43/DBS/000238 awarded by the Faculty of
Health Sciences, Jagiellonian University Medical College, Cracow, Poland.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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