Understanding the molecular mechanism associated with reversal of oral submucous fibrosis targeting hydroxylysine aldehyde-derived collagen cross-links

Smitha Sammith Shetty1, Mohit Sharma2, Shama Prasada Kabekkodu3, NV Anil Kumar4, Kapaettu Satyamoorthy3, Raghu Radhakrishnan5
1Department of Oral Pathology, Faculty of Dentistry, Melaka Manipal Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
2Department of Oral Pathology, Sudha Rustagi College of Dental Sciences and Research, Faridabad, Haryana, India
3Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
4Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, Karnataka, India
5Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
DOI: 10.4103/jcar.JCar_24_20

Fibrosis is a pathological state characterized by excessive deposition of the extracellular matrix components leading to impaired tissue function in the affected organ. It results in scarring of the affected tissue akin to an over-healing wound as a consequence of chronic inflammation and repair in response to injury. Persistent trauma of susceptible oral mucosa due to habitual chewing of betel quid resulting in zealous healing of the mucosal tissue is one plausible explanation for the onset of oral submucous fibrosis (OSF). The irreversibility and resistance of collagen to degradation and its high potential to undergo malignant change are a major reason for morbidity in OSF. Hence, early diagnosis and timely treatment are crucial to prevent the progression of OSF to malignancy. This review focuses on the mechanistic insight into the role of collagen cross-links in advancing fibrosis and possible therapeutic targets that bring about a reversal of fibrosis. These options may be beneficial if attempted as a specific therapeutic modality in OSF as is in organ fibrosis. The upregulation of lysyl oxidase and lysyl hydroxylase has been shown to exhibit the higher levels of the hydroxylysine aldehyde-derived cross-links in fibrosis and tumor stroma promoting the tumor cell survival, resistance, and invasion. The in silico analysis highlights the potential drugs that may target the genes regulating collagen crosslinking.

Keywords: Anti-fibrotic targets, collagen cross-links, fibrosis, oral submucous fibrosis, repair, treatment, wound healing