Review Article

Pathophysiology of keratinization
Priya Nimish Deo, Revati Deshmukh

Abstract Cytoskeleton of a cell is made up of microfilaments, microtubules and intermediate filaments. Keratins
are diverse proteins. These intermediate filaments maintain the structural integrity of the keratinocytes.
The word keratin covers these intermediate filament-forming proteins within the keratinocytes. They are
expressed in a specific pattern and according to the stage of cellular differentiation. They always occur in
pairs. Mutations in the genes which regulate the expression of keratin proteins are associated with a number
of disorders which show defects in both skin and mucosa. In addition, there are a number of disorders
which are seen because of abnormal keratinization. These keratins and keratin-associated proteins have
become important markers in diagnostic pathology. This review article discusses the classification, structure,
functions, the stains used for the demonstration of keratin and associated pathology. The review describes
the physiology of keratinization, pathology behind abnormal keratin formation and various keratin disorders.

Keywords: Keratinization, disorder, marker

Address for correspondence:

E-mail: priyanimishdeo@gmail.com
Received: Accepted:

INTRODUCTION

2. Secondary keratins – Produced by epithelial cells in

derived from the Greek word meaning horn. Historically
the term “keratin” stood for all of the proteins extracted

Subsequently, it was realized that keratin is actually a Based on biochemical properties

and other enzyme proteins derived from epithelial cells.

These keratins are characteristically found only in the
Based on molecular weight
Low – Glandular and simple
[1]

Based on the preferential synthesis

1. Primary keratins – keratins which are always Based on distribution
synthesized by the epithelial cells on a regular basis. Soft – Skin and mucosa

Access this article online

Quick Response Code:
Website:
www.jomfp.in

For reprints contact:

DOI:
How to cite this article: Deo PN, Deshmukh R. Pathophysiology of

86 © 2018 Journal of Oral and Maxillofacial Pathology | Published by Wolters Kluwer - Medknow
 Deo and Deshmukh: Pathophysiology of keratinization

CHEMICAL STRUCTURE OF KERATIN Table 1: Different stains for keratin

Stain Color of keratin
Each keratin is characterized by a chain of amino acids as Hematoxylin and eosin Pink
the primary structure of the keratin protein, which may vary Mallory stain Orange
Ayoub shklar stain Brilliant orange
in the number and sequence of amino acids, as well as in Phloxine tartrazine method Red
et al. 2007). The Modified Papanicolaou Magenta red
Gram stain Blue
Aldehyde fuchsin Purple
et al Congo red method Orange red
Performic acid-methylene blue/alcian blue Blue
All proteins that form intermediate filaments have a Thioflavin T fluorescent technique Yellow fluorescence
Auramine rhodamine fluorescent method Yellow fluorescence

head domain, a central - helical rod domain and

of maturation during which the cells produced by the
mitotic division in the basal layer migrate to the surface
divided into three parts, i.e., the head domain (toward the where they are shed off and are replaced by the maturing
cell population. This process of maturation follows two
and the tail domain. Each of these three domains is divided
into subdomains. Domains and subdomains are determined
by the amino acid sequence of the keratin and serve various
population and maturing population. The progenitor
population consists of stem cells and amplifying cells.
complexes or to signaling molecules.[2] After each cell division, the daughter cell either enters
the progenitor population again or enters the maturing
FUNCTIONS OF KERATIN compartment. Once it enters the maturing compartment,
the keratinocyte undergoes differentiation and becomes
committed to biochemical and morphologic changes. At
mitotic activity of epithelial cells
with densely packed protein contained within a toughened
epithelial cells and tissues to sustain mechanical stress, cell membrane is formed. After reaching the surface, it is
maintain their structural integrity, ensure mechanical shed off, a process called desquamation. This process of
resilience, protect against variations in hydrostatic migration of an epithelial cell from the basal cell layer to
pressure and establish cell polarity the surface is called maturation. The time taken by a cell
to divide and pass through the entire epithelium is called
cell transport, cell compartmentalization and cell
differentiation
in the cheek.
signals and have the ability to modulate protein
synthesis and cell size in epithelial cells These epithelial cells are composed of a cytoskeleton which

DIFFERENT STAINS USED FOR KERATINS

because their diameter is intermediate (7–11 nm)

Routine H and E staining demonstrates keratin, but it is

structures with this routine stain. Some special stains

help to detect and differentiate keratins better from other
The cells of the basal layer are the least differentiated and
connective tissue components. These special stains are
contain the typical cellular organelles and are called the
summarized in Table 1.

PHYSIOLOGY OF KERATINIZATION mitosis, thus providing new cells. The cells once they
leave the basal layer become determined for maturation.
The adjacent cells are connected to each other by
of cells called keratinocytes. These cells undergo a process desmosomes which are specialized intercellular junctions.

Journal of Oral and Maxillofacial Pathology | Volume 22 | Issue 1 | January - April 2018 87
 Deo and Deshmukh: Pathophysiology of keratinization

These desmosomes contain two types of proteins – the attractive forces which operate between all polypeptide
transmembranous proteins and proteins of the attachment chains, although the presence of appreciable number of
plaque. The transmembranous proteins are the desmogleins
and desmocollins which are the members of the cadherin and extent of keratinization of the epithelium depends
family. The attachment plaque proteins are desmoplakin, on a number of different processes during differentiation
plakoglobin, plakophilin, envoplakin and periplakin. Above such as synthesis, breakdown and dehydration which
the basal cell layer rest polyhedral cells which occupy larger determine the classification of the epithelium into
volume and this layer is called the stratum spinosum. keratinized or nonkeratinized.[10] Thus, keratin is not a
cellular secretion, but it is the end result of transformation
of ectoderm-derived epithelial cells called keratinocytes
into the attachment plaque (intracellular portion of the into squame of keratin. When these squame are worn away
desmosomes). The protein-synthesizing activity of the or desquamate from the surface, they are replaced by the
spinous cell layer is more, indicating its biochemical changes process of keratinization.
and commitment to keratinization. The cells of the stratum
Aging is associated with decreased rate of metabolic activity,
and contain basophilic keratohyalin granules. The nuclei but studies on epithelial proliferation and rate of tissue
turnover in healthy tissue are inconclusive. Histologically,
are more dense and seen in association with the the epithelium appears thinner, and a smoothing of the
keratohyalin granules. Lamellar granule or Odland body or epithelium connective tissue interface results from the
keratinosome, a small organelle, forms in the upper spinous [9]

[11]

cell layers and form the permeability barrier. At the same

time, the inner unit of the cell membrane thickens forming

this structure such as involucrin, loricrin, periplakin and pathway to decrease keratinocyte proliferation and to
envoplakin. The stratum corneum is made up of keratinized increase cell differentiation

Here, all nuclei and other organelles such as ribosomes growth factor- exert a mitogenic effect on basal cells
and mitochondria have disappeared. The keratohyalin

mucosa

keratinized cell becomes compact, dehydrated and covers

a greater surface area than does the basal cell from which
[8,9] proliferation
acidophilic layer of the keratinized epithelium consists
keratinocyte proliferation by stimulating the production
of the sulfur-containing amino acid cysteine. This protein
is termed keratin, although it is important to remember
that keratins differ widely in composition between tissues originating in connective tissue that elicits keratinocyte
and between species and the term refers to a family of proliferation and migration

1972). Electron micrographs show that keratin consists

basal and suprabasal cells

appearing as light structures against a darker background to undergo mucous metaplasia, a condition wherein
of the matrix in fully keratinized cells, an appearance

opposite effect, i.e., squamous metaplasia

88 Journal of Oral and Maxillofacial Pathology | Volume 22 | Issue 1 | January - April 2018
 Deo and Deshmukh: Pathophysiology of keratinization

differentiation.

HOW APOPTOSIS AND DESQUAMATION DIFFER? PATHOLOGY OF KERATINIZATION

Pathology of keratinization shows various patterns. These

death of the keratinocytes (Houben et al., 2007). This pathologies can be due to defect in genes which code for
epidermal programmed cell death is different from the keratin proteins or there are lesions which demonstrate
programmed cell death in apoptosis because the extra- and abnormal keratinization histopathologically due to
intra-cellular signaling cascade that is characteristic of different etiological factors. There could be increased
apoptosis is not activated (Lippens et al keratinization, decreased keratinization, or abnormal
et al keratinization.
from apoptosis because the terminally differentiated cells
are dead but intact and not cell fragments as in apoptotic Hyperkeratinization is the defect of epithelial cells.
bodies (Weil et al., 1999). The only genuine apoptosis
in the epidermis occurs in the so-called sunburn cells,
which are basal cells that are damaged by ultraviolet B disturbed because of an excess of keratin formation and
rays (Denecker et al., 2007). Apoptosis can take place
at any stage of cell differentiation, but the process of occurs as a secondary reaction to chronic irritation or
some infection or malignancy. Hyperkeratinization which
occurs because of chronic irritation is due to higher rate
not a type of apoptosis (Denecker et al., 2008). However, of proliferation of the epithelial cells.

cornifying cells in the transition zone between the granular Decreased keratinization or lack of keratin production is
et al., 1999). The due to failure of the epithelial cells to undergo complete
differentiation and maturation to the point of keratin
the cell nucleus and of the organelles (Weil et al., 1999). The formation.

cornifying keratinocytes of the epidermis (Demerjian et al., Dyskeratosis is premature keratinization which occurs
2008), is not expressed in the keratinizing but not cornifying in individual cells or group of cells in different strata
keratinocytes of the oral epithelium (Lippens et al., 2000). of the epithelium, before they reach the surface. These
cells become separated from the adjacent cells. These
the nail matrix (Jäger et al., 2007), indicating differences dyskeratotic cells are large and round with a deep
in the processes of soft versus hard keratinization and eosinophilic cytoplasm and a hyperchromatic nucleus.
[2]
A benign keratin pearl is surrounded by cells which are
Cytokeratin expression in normal oral mucosa
there is lack of cohesion among the epithelial cells due to

and 19[9,12] [ 1].

Cytokeratin expression in odontogenic tissues

secreting ameloblasts. Hertwig’s epithelial root sheath

[1]

Cytokeratin expression in normal salivary gland tissues a b

Figure 1: (a) Expression of cytokeratins in the oral keratinized
epithelium. (b) Expression of cytokeratins in oral Nonkeratinized
(Buccal) epithelium

Journal of Oral and Maxillofacial Pathology | Volume 22 | Issue 1 | January - April 2018 89
 Deo and Deshmukh: Pathophysiology of keratinization

malignant changes, the cells get arranged in a concentric

manner. As the fate of a squamous cell is to form keratin,
these cells lay down keratin in a concentric manner and
then appear as keratin pearls which are known as malignant significantly expressed in odontogenic keratocysts as

accumulations of keratin made by malignant squamous in suprabasal layers of all odontogenic cysts.[18]
cells and are present in concentric layers in between the
squamous epithelium. Cytokeratin expression in odontogenic tumors
Odontogenic tumors with epithelial component frequently
These different patterns of keratin formation depend on
et al. proved that most of the tumors of
frictional keratosis or in mild leukoplakia if the underlying mesenchymal origin such as odontogenic myxoma do not
stimulus is removed, the change in the mucosa is reverted
markers for tumors of odontogenic epithelial origin.[19,20]
premature keratinization of the cells before they undergo
complete differentiation. Cytokeratin expression in salivary gland tumors

ORAL KERATINIZATION DISORDERS diagnosis between myoepithelioma/myoepithelial

carcinoma or “undifferentiated carcinoma” and
A number of lesions occur in the oral cavity which show nonepithelial tumors. According to a study conducted
an abnormal pattern of keratinization. These include et al
oral geno-dermatosis to mild self-limiting lesions to
in all malignant salivary gland tumors.[21]
cysts and tumors. All these lesions show some defect in
1].[1] SUMMARY AND CONCLUSION

The genetic disorders of keratin formation are due to A cell synthesizes different subsets of keratin during
mutations in genes which code for different keratin the process of maturation, for example., basal cells
proteins. These lesions and the associated mutations are
mentioned in Table 2.

ACQUIRED KERATIN DISORDERS

pattern of keratin expression of a particular cell allows
There are various lesions which demonstrate abnormal one to identify the origin of the cell and its stage of
keratinization histopathologically. They include reactive differentiation and thus helps to characterize the neoplasm.
lesions, immune-mediated lesions, infections, preneoplastic
and neoplastic diseases as well as cysts containing keratin Table 2: Genetic disorders of keratin formation
and miscellaneous lesions. There is a considerable Lesion Pathogenesis
histopathological similarity between these disorders. White sponge nevus Mutations in keratin genes 4 and 13
Pachyonychia congenita Jadassohn-Lewandowsky type - mutations
These lesions show a broad spectrum of histopathological in keratin 6a or 16 gene
changes such as hyperkeratosis, lack of keratinization, Jackson-Lawler type - mutations in keratin
individual cell keratinization and keratin pearl formation, 6b or 17 gene
Epidermolysis bullosa Mutations in genes coding for keratin
while some odontogenic lesions show the presence of 5 and 14, laminin, Type VII collagen,
ghost cells which are believed to be an abnormal form of hemidesmosomal attachment proteins
keratinization. Dyskeratosis congenita Rare genodermatosis inherited as
X-linked recessive trait
Hereditary benign Autosomal dominant skin disorder,
EXPRESSION OF CYTOKERATINS IS STUDIED intraepithelial caused by mutations of ATP2A2 gene
BY MANY RESEARCHERS AND IS EVIDENT IN dyskeratosis
PATHOLOGIES SUCH AS ODONTOGENIC CYSTS, Darier’s disease A lack of cohesion among the surface
ODONTOGENIC TUMORS AND SALIVARY GLAND epithelial cells, mutation of a gene that
TUMORS encodes intracellular calcium pump has
been identified as the cause of abnormal
desmosomal organization
Cytokeratin expression in odontogenic cysts Pemphigus Autoantibodies are directed against the
epidermal cell surface glycoproteins
desmoglein 3 and desmoglein 1
positive expression in dentigerous and radicular cysts.
90 Journal of Oral and Maxillofacial Pathology | Volume 22 | Issue 1 | January - April 2018
 Deo and Deshmukh: Pathophysiology of keratinization

Flow Chart 1: [1]

are used routinely as markers for diagnosis of carcinomas.

th

transforming itself into keratin, both physiologically and

th

synthesis. Structure and function of normal human oral mucosa. Oral

opened a Pandora’s box, which is of great importance in

diagnosis as well as prognosis.

Financial support and sponsorship

Conflicts of interest
et al.

REFERENCES

1. Rao RS, Patil S, Ganavi BS. Oral cytokeratins in health and disease. J cytokeratin expression in the different cell types of salivary gland

2. Bragulla HH, Homberger DG. Structure and functions of keratin

17. Shafer, Hine, Levy. Shafer’s Textbook of Oral Patholog y.

Papanicolaou stain with ayoub-shklar and haematoxylin-eosin stain for

et al.

Journal of Oral and Maxillofacial Pathology | Volume 22 | Issue 1 | January - April 2018 91