|Year : 2019 | Volume
| Issue : 3 | Page : 153-158
Cathepsins in oral diseases
K Ajay Benarji1, K Roja Lakshmi2, Hasini Nelakurthi2, Pothuraju Haritha3, Rudraraju Amrutha4
1 Department of Oral Pathology, Drs. Sudha and Nageswara Rao Siddhartha Institute of Dental Sciences, Gannavaram, Andhra Pradesh, India
2 Department of Oral Pathology, GSL Dental College and Hospital, Rajahmundry, Andhra Pradesh, India
3 Department of Oral Pathology, Panineeya Dental College, Hyderabad, Telangana, India
4 Department of Oral Pathology, Navodaya Dental College, Raichur, Karnataka, India
|Date of Submission||19-Apr-2019|
|Date of Acceptance||19-Aug-2019|
|Date of Web Publication||17-Oct-2019|
Dr. K Roja Lakshmi
Department of Oral Pathology, GSL Dental College and Hospital, Rajahmundry, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Cathepsins are a class of globular lysosomal proteases known to be responsible for protein degradation. In addition to proteolysis they have many biological roles such as apoptosis wound healing angiogenesis, proenzymatic activation, bone remodelling and resorption. Cathepsins role has been implicated in the pathogenesis of systemic diseases such as cancer, bronchial asthma, atherosclerosis, neurological disorders, rheumatoid arthritis and osteoarthritis. This review highlights the role of cathepsins in various oral diseases like periodontitis, odontogenic cysts, ameloblastomas, salivary gland tumours and oral malignant melanoma.
Keywords: Cancer, caries, cathepsin, oral, periodontitis, proteases
|How to cite this article:|
Benarji K A, Lakshmi K R, Nelakurthi H, Haritha P, Amrutha R. Cathepsins in oral diseases. J NTR Univ Health Sci 2019;8:153-8
| Introduction|| |
Proteases are the type of enzymes which catalyze peptide bond hydrolysis and help in protein digestion. These enzymes are ubiquitous in nature and control numerous biological process. They regulate cell proliferation, angiogenesis, blood clotting, wound repair, necrosis, and apoptosis. There are 84 families of proteases which are classified into serine, aspartic, cysteine, and metalloproteases based on their catalytic activity. Later on, the term “cathepsin” was proposed by Willstaetter and Bamann especially for lysosomal proteases active in slightly acidic pH. Cathepsins are categorized as (1) serine proteases: cathepsins A and G; (2) aspartic proteases: cathepsins D and E; and (3) cysteine proteases: cathepsins B, C, F, H, K, L, O, S, V, X, and W. These enzymes play a key role in multiple physiological processes such as apoptosis, antigen presentation, proenzyme activation, wound healing, bone remodeling, neuropeptide, and hormone processing. To maintain tissue homeostasis, the cathepsins' expression is controlled by endogenous inhibitors, such as cystatins, serpins, and thyropins. The release of cathepsins in inactive form and the presence of endogenous inhibitors help in maintaining physiological equilibrium. Their dysregulation has been associated with various diseases such as atherosclerosis, osteoporosis, arthritis, neurological disorders, and cancer. In cancer, their role in tumor angiogenesis and metastasis has gained attention as they represent excellent targets for therapeutic interventions. Cathepsins are also produced by pathogenic bacteria which act as virulence factor and result in development of diseases.
| Cathepsin Structure Activation and Inhibition|| |
The cathepsins are synthesized as inactive zymogen; prodomain present in zymogen blocks the active sites and prevents substrate hydrolysis. For activation, zymogen switch is required wherein the prodomain is removed. Within endoplasmic reticulum, the signal peptide present in inactive state gets cleaved and these proenzymes are glycosylated which are then transported to Golgi apparatus. In Golgi apparatus, phosphorylation of mannose residues occurs and mannose 6 phosphate is formed which reaches lysosomes through mannose 6 phosphate receptor pathway. In late endodosome, acidification occurs resulting in disassociation of prodomain from active site and cathepsins become active. Prodomain thus acts as an autoinhibitor for cathepsins. The complete activation takes place in lysosomes through autocatalytic or transactivation mechanisms. Acidic environment and presence of glycosaminoglycans hasten the activation process. Proteolytic activation is mediated by matrix metalloproteinases (MMPs).
Cathepsin activity can be regulated by inhibition mainly by distortion and blocking of active site. Endogenous inhibitors such as cystatins, thyropins, and serpins inhibit cathepsin. Cystatins constitute a largest group among endogenous cathepsin inhibitors targeting mainly cysteine proteases. Cystatins inhibit cysteine proteases intracellularly by partially blocking the active center through noncovalent interaction. The cystatin family is further grouped into type 1 cystatin (stefins), type 2 cystatin (cystatins), and type 3 cystatin (kininogens). Serpins are capable of inhibiting serine proteases and cysteine proteases. Their inhibitory mechanism is by degradation of active site. Thyropins inhibit cysteine proteases. There are no known endogenous inhibitors for aspartate proteases till date.
| Cathepsin Localization and Functions|| |
It is the most abundant and widely expressed cathepsin which is encoded by the CTSB gene mapped to chromosome 8p22. It is found at high levels in macrophages and gingival crevicular fluid. Cathepsin B has been immunolocalized to granular duct cells in the rat submandibular gland and to gingival fibroblasts. It is mainly involved in cellular processes such as proteolysis, antigen processing, and apoptosis. Cathepsin B causes degradation of collagen and other noncollagenous matrix proteins, thus playing a key role in resorption lacunae formation in deciduous teeth. It is seen in human dentin–pulp complex. Cathepsin B has also been identified in ameloblasts.
Cathepsin C (CTSC) also known as dipeptidyl peptidase I is encoded by the CTSC gene, located at chromosome 11q14. It is an exogenic salivary peptidase which cleaves off dipeptides from the N-terminal of peptides. It plays a major role in the activation of platelet factor XIII and many serine proteases in inflammatory cells.
Cathepsin D is a lysosomal aspartyl protease which is involved in the metabolic degradation of protein, polypeptide hormones, and growth factors. In certain epithelial tissues, it acts as mitogen and helps in tissue remodeling and renewal. In the oral cavity, it is present in the gingival fluid and immunolocalized in rat junctional epithelium and oral mucosa.
It is produced mainly by neutrophils and plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites. Furthermore, it is involved in platelet activation leading to platelet aggregation and clot formation.
This protein, a member of lysosomal cysteine proteases, is expressed predominantly in osteoclasts and is involved in bone remodeling and resorption. Through its catabolic action, it can break down bone and cartilage. In deciduous tooth, cathepsin K localized in the odontoclasts is responsible for extracellular degradation of dentin collagens during physiological root resorption.
Cathepsin L is involved in the cleavage of a wide range of substances including extracellular matrix such as fibronectin, collagen, and laminin. Cathepsin L is known to participate in turnover of intracellular or endocytosed proteins, antigen processing and presentation, bone resorption, and various other processes.
Cathepsins B, L, N, S, and K are referred to as collagenolytic cathepsins as they can degrade collagen. Cathepsins involved in the pathogenesis are depicted in [Figure 1].
| Cathepsins in Oral Diseases|| |
Dental caries is a microbial disease characterized by demineralization of inorganic and dissolution of organic matrix. MMPs are mainly implicated in the pathogenesis of caries. Cysteine cathepsins are colocalized with MMPs and thought to activate the latent MMPs and promote caries progression. Cathepsin B exhibited stronger immunoreactivity in carious dentin when compared with the sound dentin. The levels of cathepsin B correlated with increasing depth in carious dentin. In a study by Vidal et al., the author speculated that an increase in cathepsin K in carious dentin may be related to modulation of transforming growth factor-β.
Periapical lesions develop around tooth apex as a sequelae of pulpal inflammation. They manifest as a result of host immune response against bacteria. It may result in resorption of hard tissues and destruction of periapical tissues. Sometimes, certain factors in the inflamed tissues can result in failure of endodontic treatments. In these lesions, osteoclasts play a key role in the degradation of bone matrix. Cathepsin K is strongly expressed by osteoclasts in these lesions. In a study by Gao et al., by knocking down the cathepsin K enzyme through adeno-associated virus (AAV)-RNAi vector, reduced inflammation and bone destruction are noted.
In periodontitis, Porphyromonas gingivalis is the main etiological agent. The balance between activity of cathepsins and their endogenous inhibitory mechanisms is disrupted by this bacterium. Thus, these enzymes through their proteolytic activity may degrade the periodontal tissue. Hence, higher levels of cathepsins B, D, G, H, K, and L are seen when compared with the controls. Cathepsin G also showed higher activity in adult periodontitis when compared with controls. This enzyme may break down the periodontal tissues directly and indirectly through proteolytic activation of latent neutrophil procollagenase (promatrix metalloproteinase 8) and can lead to periodontitis. These enzymes may act as biomarkers of periodontal inflammation as they correlate with pocket depth.,
Papillon–Lefevre syndrome is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe early-onset periodontitis that result in the premature loss of the teeth. Mutations in the CTSC gene are responsible for this syndrome. CTSC plays a key role in phagocytosis. In patients affected with this syndrome, immunological findings such as decreased neutrophil, monocyte chemotaxis, impaired phagocytosis, and altered superoxide production are noted. Polymorphonuclear leukocyte (PMNL) cell capacity fails to eliminate Aggregatibacter actinomycetemcomitans resulting in periodontitis.
Peri-implantitis inflammatory process affects the tissues around dental implants which often result in implant loss. Yamalik et al. observed that the levels of cathepsin K activity are more in peri-implantitis and peri-mucositis when compared with healthy peri-implant tissues. Mogi and Otogoto observed co-relation between RANKL and cathepsin K levels. These findings suggest that increased expression of RANKL triggered active osteoclast formation which led to more production of cathepsin K resulting in bone resorption.
Oral lichen planus
Oral lichen planus is a chronic mucosal disease mediated by T cells. In psoriasis, cathepsin K inhibitor has shown to inhibit TLR-mediated cytokine release by dendritic cells. In oral lichen planus, there is TLR4 and TLR9 induction, and the coexpression of cathepsin K was seen in some dendritric cells. Hence, it is suggested that in oral lichen planus, cathepsin K is involved in the upregulation of cytokine activity by dendritic cells. Cathepsin K levels are higher in patients with oral lichen planus when compared with controls, and tracolimus treatment reduced the levels of cathepsin K indicating its role in pathogenesis of OLP.
Giant cell lesions and tumors
Giant cell tumor is benign neoplasm of bone characterized by localized osteolysis. In giant cell tumors, cathepsin K is detected exclusively in osteoclast-like giant cells supporting the hypothesis that it is the predominant factor in osteolysis. In giant cell lesions, staining pattern of cathespin K was strong in 85% of peripheral giant cell granulomas, 60% of giant cell tumors, and 57% of central giant cell granulomas. Moreover, abundant coexpression of vacoular H+-ATPase creates acidic environment required for cathepsin K activity. Cathepsin L is the other protease found in giant cell lesions and tumors. Its staining pattern is moderate in peripheral giant cell granulomas and weak in central giant cell granulomas and giant cell tumors. Unlike cathepsin K, all mononuclear cells were immunostained in addition to giant cells, in all entities for cathepsin L expression. The exact pathogenesis of this enzyme is not known.,
Odontogenic cysts and tumors
Odontogenic cysts and tumors are the lesions arising from tooth apparatus which are usually aggressive invading the surrounding bone and tissues. In a study by Yogesh et al., staining intensity of cathepsin D in each layer and stroma/capsular wall between various odontogenic cysts was observed. Different staining patterns were observed in the epithelial lining and stroma. The intensity of staining progressively increased from dentigerous cyst through the radicular cyst to the odontogenic keratocyst (OKC). This pattern of increasing expression seemed to correlate with increasing aggression. Intense granular staining was observed at the separation zone of OKC. This finding suggests that cathepsin B could be one of the enzymes important in separation of epithelium and connective tissue in OKC. In the same study, staining was observed among different variants of ameloblastomas. Marked staining of the granular cells and spillage in granular cell ameloblastoma compared with others may explain its aggressive behavior, recurrence, and metastatic potential.
Salivary gland tumors
Salivary gland tumors are the most heterogeneous tumors histologically among head and neck tumors. Vigneswaran et al. observed higher expression of cathepsin D in malignant salivary gland neoplasms when compared with benign tumors. Intense expression of cathepsin D was observed in mucoepidermoid carcinoma and adenoid cystic carcinoma when compared with pleomorphic adenoma suggesting it to be a marker for invasive potential and aggressive behavior. In a study by Zhang et al., they suggested that it contributes to perineural invasion of adenoid cystic carcinoma.
Cancer is a multistage process involving changes at genetic level. Invasiveness and metastasis are controlled by various proteases. Cathepsins degrade extracellular matrix thereby disrupting intercellular communications. Cathepsins promote apoptosis by triggering caspases (intracellular cathepsins) or by shedding of Fas death receptors (extracellular cathepsins).
Cathepsin B may contribute to uncontrollable proteolysis and participate in dissolution and remodeling of connective tissue and basement membrane in the process of tumor growth, invasion, and metastasis. Cathepsin B expression correlated with positive lymph node metastasis and higher tumor grade, thus demonstrating its role in malignant progression of tongue cancer., Its levels are also overexpressed in HPV-positive lesions of oral squamous cell carcinoma. Hypoxic conditions can increase the expression of cathepsin B which correlated with tumor grade and alteration in localization of the enzyme. It is observed that cathepsin B enhances the activity of other class of proteases such as cathepsin D, MMP, and plasminogen activators.
An increase in cathepsin D expression was observed during the transformation of dysplasia to oral squamous cell carcinoma. The expression correlated with cancer invasiveness and progression. Alteration of location of cathepsin D from the lysosome to the tumor invasive front is noted and its expression correlated with p53 gene abnormalities. Cancer cells often secrete procathepsin D which acts as a mitogen stimulating proinvasion and metastasis.,
In tongue carcinomas, cathepsin K is expressed in invasive TM front indicating a protective role in the complex progression of tongue cancer., Cathepsin K through its collagenolytic activity degrades extracellular matrix and also modulates cell adhesion by enhancing CD29/β1 integrin adhesion receptors.
In oral cancer, overexpression of cathepsin L is more likely to result in the progression of tumor. In a study by Macabeo-Ong et al., they found that cathepsin L levels were lower in nonprogressive dysplasia when compared with progressive dysplasia and oral cancer. The expression of cathepsin L correlated with lymph node metastasis and poor prognosis, suggesting its role as potent biomarker for cancer prognosis.
| Conclusion|| |
Cathepsins have a key role in pathogenesis of several oral diseases. They can act as biomarkers in various oral diseases. Future research and investigation is needed to better understand the exact pathogenic mechanism of cathepsins in oral diseases. This information may in turn help to target these molecules for therapeutic purposes.
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Conflicts of interest
There are no conflicts of interest.
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