Oral submucous fibrosis: pathogenesis and therapeutic approaches

Abstract

Oral submucous fibrosis (OSF), characterized by excessive deposition of extracellular matrix (ECM) that causes oral mucosal tissue sclerosis, and even cancer transformation, is a chronic, progressive fibrosis disease. However, despite some advancements in recent years, no targeted antifibrotic strategies for OSF have been approved; likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined. In this review, we briefly introduce the epidemiology and etiology of OSF. Then, we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors, secretion function, and activation of ECM-producing myofibroblasts. In addition, we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF. Finally, we summarize strategies to interrupt key mechanisms that cause OSF, including modulation of the ECM, inhibition of inflammation, improvement of vascular disturbance. This review will provide potential routes for developing novel anti-OSF therapeutics.

Fig. 1

Timeline for key events in studies of OSF research. Orange boxes summarize etiological studies of OSF; Blue boxes show relevant studies of OSF pathogenesis

Fig. 2

The pathogenesis of OSF. The damage of oral epithelial cells through the production of ROS or through the dysfunction of epithelial cells, such as arrested cell cycle and proliferation inhibition work to promote fibrosis. In addition, the injured epithelial cells also promote EMT process by activating EMT-related signaling pathways. The vascular endothelial injury caused by arecoline also leads to the production of ROS, thus promoting EndMT by activating YAP/TAZ and can eventually leads to fibrosis. Infiltrated immune cells secrete cytokines induced by injury, local ischemia, hypoxia, and SASPs, which were derived from fibroblasts in senescence conditions, thus promoting fibrosis. Leukocytes from circulation may be recruited by chemokines to inflamed areas to secrete profibrotic cytokines. Furthermore, secreted mediators such as TGF-β1, PDGF, bFGF cause fibroblasts activation, which produces excessive ECM. Injured endothelial cells also induce autophagy, fibrinolysis system disorder, and abnormal coagulation function, which leads to microvascular occlusion and further accelerates the process of fibrosis

Fig. 3

Pharmacological strategies may lead to OSF regression. (1) Modulation of extracellular matrix deposition that control OSF development is an antifibrotic approach: Local injection of hyaluronidase, collagenase, and chymotrypsin is used to reduce the levels of ECM deposition by the hydrolysis of hyaluronic acid, esters, and peptide bonds. (2) Regulation of inflammatory response. Inhibition of inflammation and prevention of activation of MFB by the injection of immunomodulators such as steroids, or anti-fibrotic cytokines. (3) Ameliorating peripheral microcirculation disturbance with established drugs to improve vascular occlusion and fibrinolysis system disorders will attenuate OSF progression, with multiple optimized strategies under development. (4) Other therapeutic strategies are under development to inhibit the collagen aggregation, including antioxidants and natural medicine such as tanshinone and curcumin that act on TGF-β/Smad signaling. BG/HA have been used to inhibit inflammatory responses and promote angiogenesis. DPSCs might have beneficial therapeutic effects via inhibiting crosstalk between epithelial cells and T cells, although further studies are needed