Oral submucous fibrosis: Regulatory mechanism of collagen metabolism and management

Oral submucous fibrosis (OSF) is a chronic and insidious potentially malignant disorder characterized by progressive fibrosis of the oral submucosa. It is recognized to be an irreversible disease of multifactorial origin, with limited therapeutic options due to incomplete understanding of its pathogenesis. Increased collagen synthesis or decreased collagen degradation is vital for the development of OSF. This review mainly introduces the key regulatory mechanism of collagen metabolism. Prolonged use of areca nut is arguably the major causative agents for OSF, which is vital for the myofibroblast transdifferentiation, fibroblastic proliferation, collagen synthesis, and resistance to collagenases. Chemical constituents of areca nut, and these components induced changes in epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodelling, inflammatory cytokines and growth factors, autoimmunity, and aberrant non-coding RNAs, are pivotal regulating factors for the myofibroblast activity and collagen metabolism in OSF. Oxidative stress following cell injury by areca nut extract, represented by reactive oxygen species (ROS) production, regulates ECM, EMT and cell cycle in OSF. Other factors such as nutrition, local stimulating factors and genetic susceptibility are also involved in the disease onset and progression. This paper summarizes both etiological factors and pathogenetic mechanisms underlying the collagen metabolism dysregulation in OSF, which provides new molecular targets and further research directions for the management of OSF. • Increased collagen synthesis and/or decreased collagen degradation initiate OSF. • Chemical constituents of areca nut and these components-induced changes contribute to pathogenesis. • Aberrant non-coding RNAs regulate fibrotic processes and EMT. • Genetic susceptibility, nutrition, and autoimmunity aid in the disease onset and progression. • Targeted antifibrotic strategies are vital for the management of OSF.