Introduction

Cytokeratins, also known as keratins, are typical intermediate filament proteins in epithelial cells, exhibiting high molecular diversity. As part of the epithelial cell cytoskeleton, cytokeratins are crucial for maintaining the mechanical stability and integrity of epithelial cells and tissues. Moreover, increasing evidence suggests that cytokeratins can target downstream genes, regulating various cellular biological functions such as apoptosis, proliferation, migration, and wound healing. Mutations and abnormal expression of cytokeratin genes are involved in regulating a variety of diseases, including inflammation and tumors.

Early studies suggested that cytokeratins were specifically expressed in the skin, but it is now known that they are expressed in various epithelial tissues as immunoregulatory molecules. Cytokeratins play significant roles in the development of inflammation and various biological behaviors of tumors, becoming new therapeutic targets for inflammation and tumors. In recent years, with extensive research on cytokeratins in the field of oral health, their roles in oral diseases have garnered significant attention.

Structure of Cytokeratins

Cytokeratins share a homologous basic structure with all intermediate filament proteins. The central α-helical rod domain, consisting of 310-315 amino acids, is responsible for dimerization and higher-order polymerization. This domain is composed of four highly conserved regions: 1A, 1B, 2A, and 2B. The α-helix is made up of heptad repeat sequences of amino acids, where the first and fourth residues are hydrophobic, closely packed on the surface of the helix, enabling two adjacent polypeptides to form a coiled-coil structure. There is a staggered sequence in the 2B helical domain, which is associated with the reversal of the α-helix direction. Mutations that shorten the rod domain result in keratins that not only fail to assemble into filaments but also disrupt pre-existing keratin filament networks due to the highly dynamic and reversible assembly and disassembly capabilities of keratins. The four highly conserved domains are separated by non-helical linker domains (L1, L12, L2). L1 and L12, rich in glycine and proline, disrupt the α-helix more effectively than the glycine-rich L2. In keratins 5 and 14, mutations are concentrated in the L12 linker domain, disrupting the β-sheet structure of the L12 domain and preventing proper filament assembly between keratins 5 and 14. The N-terminal head and C-terminal tail regions confer individual keratin antigen specificity and include two highly homologous subdomains (H), two variable subdomains (V), and two highly charged terminal subdomains (E).

Fig. 1 Structure of cytokeratin (Awasthi P.; et al. 2016).

Types of Cytokeratin

Cytokeratins are classified into two types: low-molecular-weight or acidic type I cytokeratins, and high-molecular-weight or basic/neutral type II cytokeratins. The high-molecular-weight cytokeratins include numerous subtypes, such as CK1, CK2, CK3, CK4, CK5, CK6, CK7, CK8, and CK9, while the low-molecular-weight cytokeratins comprise CK10, CK12, CK13, CK14, CK16, CK17, CK18, CK19, and CK20. The expression of these cytokeratins varies among different organs, making them organ-specific. The molecular weight of cytokeratins decreases with an increase in their numerical order, with cytokeratin 1 having the highest molecular weight and cytokeratin 19 the lowest.

In the oral cavity, the types and distribution of keratins show significant differences across various tissues and cells. For example, the keratins present in the oral mucosa differ from those in the epidermis of the skin. Common keratins in the oral mucosa include K4 and K13 (non-keratinized epithelium) and K6 and K16 (keratinized epithelium), while the primary keratins in the skin are K1 and K10. Additionally, specific tissues in the oral cavity, such as the gingiva and hard palate epithelium, have their unique keratin expression patterns. Changes in the expression of these keratins can reflect the functional state and health of these tissues.

The role of cytokeratins in the oral cavity extends beyond structural support and mechanical protection. They are involved in the differentiation, proliferation, and migration of oral epithelial cells, influencing the regeneration and repair of oral tissues. For instance, during the healing process of oral ulcers, the redistribution and regulation of keratin expression are crucial for rapid wound repair. Moreover, keratins in the oral epithelium are closely associated with the occurrence and development of several oral diseases, such as oral cancer, oral leukoplakia, and other oral mucosal lesions.

Cytokeratins and Oral Diseases

Cytokeratins and Periodontitis

Periodontitis is a chronic infectious disease characterized by inflammation of the periodontal supporting tissues, manifested by gingival redness, periodontal pocket formation, attachment loss, and alveolar bone resorption. It is the primary cause of tooth loss in adults. Gingival epithelium, as the first line of defense against periodontal pathogens, plays a crucial role in the development and progression of periodontitis.

Gingival epithelial cells, as a significant component of gingival epithelium, possess strong self-renewal and repair capabilities. Recent studies have shown a connection between abnormal cytokeratin expression in gingival epithelial cells and the etiology and progression of periodontitis. Therefore, understanding the mechanisms through which cytokeratins impact periodontal tissues is essential for a deeper understanding of periodontitis pathogenesis.

Cytokeratins and Oral Cancer

In recent years, as various biological functions of cytokeratins have been discovered, their roles in cancer development have attracted increasing attention. Reports have linked changes in cytokeratin expression in oral epithelial cells to the development of oral squamous cell carcinoma (OSCC). K8/K18 is primarily expressed in simple epithelial cells and is nearly absent in stratified oral squamous epithelial cells. However, studies have found that K8/K18 expression is significantly upregulated in cancerous tissues of OSCC patients and plays a role in regulating tumor progression and invasion.

Cytokeratins and Oral Mucosal Diseases

The oral mucosa is covered by stratified squamous epithelium. During epithelial renewal, epithelial cells express cytokeratins and other structural proteins to form cytoskeletal structures, which are crucial for maintaining the integrity and continuity of the mucosal epithelium. Studies have found that mutations in cytokeratin genes can lead to various oral mucosal epithelial lesions, such as leukokeratosis. Recent research has also indicated that abnormal expression of cytokeratins in mucosal epithelial cells is associated with some oral mucosal precancerous lesions in terms of etiology and disease diagnosis, with lichen planus and leukoplakia being relatively common.

Conclusion

In summary, cytokeratins play a pivotal role in maintaining the structure and function of epithelial tissues, including those in the oral cavity. Their diverse expression patterns and interactions with various cellular processes underscore their importance not only in normal tissue physiology but also in the pathogenesis of several oral diseases. The link between cytokeratin abnormalities and conditions such as periodontitis, oral cancer, and mucosal diseases highlights the potential of targeting these proteins for therapeutic and diagnostic purposes. Continued research into the specific roles of cytokeratins in oral health and disease will be essential for developing novel strategies to manage and treat oral conditions effectively.