Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Aug 13:20:9.
doi: 10.4103/jcar.JCar_24_20. eCollection 2021.

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

Smitha Sammith Shetty  1 , Mohit Sharma  2 , Shama Prasada Kabekkodu  3 , Nv Anil Kumar  4 , Kapaettu Satyamoorthy  3 , Raghu Radhakrishnan  5
Affiliations
Review

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

Smitha Sammith Shetty et al. J Carcinog. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

All the authors of the manuscript hereby state that there is no financial implication or personal relationship with other people or organization that could inappropriately influence the outcome of this work.

Figures

Figure 1
Figure 1
Mature cross-links derived from lysald and hylald pathway, (a) Dehydro-histidinohydroxymerodesmosine, (b) Histidinohydroxylysinonorleucine, (c) Hydroxylysyl pyridinoline, (d) Lysyl pyridinoline, (e) Pyrrole
Figure 2
Figure 2
Schematic diagram illustrating the lysald and hylald pathways in soft tissue and hard tissue, respectively
Figure 3
Figure 3
Schematic diagram illustrating the mechanism of collagen crosslinking in oral submucous fibrosis
Figure 4
Figure 4
Construction of gene interaction network for the genes LOX, LOXL2, PLOD2, TGFB1, and HIF1A. LOX: Lysyl oxidase, LOXL2: LOX like (LOXL) 2, PLOD2: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2- encoding LH2, TGFB1: Transforming Growth Factor Beta 1, HIF1A: Hypoxia-inducible factor 1-alpha
See this image and copyright information in PMC

References

    1. van der Slot-Verhoeven AJ, van Dura EA, Attema J, Blauw B, Degroot J, Huizinga TW, et al. The type of collagen cross-link determines the reversibility of experimental skin fibrosis. Biochim Biophys Acta. 2005;1740:60–7. - PubMed
    1. Trivedy C, Warnakulasuriya KA, Hazarey VK, Tavassoli M, Sommer P, Johnson NW. The upregulation of lysyl oxidase in oral submucous fibrosis and squamous cell carcinoma. J Oral Pathol Med. 1999;28:246–51. - PubMed
    1. Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis – A collagen metabolic disorder. J Oral Pathol Med. 2005;34:321–8. - PubMed
    1. Phulari RG, Dave EJ. A systematic review on the mechanisms of malignant transformation of oral submucous fibrosis. Eur J Cancer Prev. 2020;29:470–3. - PubMed
    1. Ekanayaka RP, Tilakarantne WM. Oral submucous fibrosis: Review on mechanisms of malignant transformation. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:192–9. - PubMed

LinkOut - more resources