Fibromodulin is up-regulated by oxidative stress through MAPK/AP-1 pathway to promote PSCs activation

Abstract Background and objectives The pathogenesis of chronic pancreatitis (CP) is unknown, and the expression of fibromodulin (FMOD) in CP tissues and the effect on the function of pancreatic stellate cells (PSCs) has been seldom studied. Our aim was to investigate the role of FMOD contributes to the pathogenesis of fibrosis by regulating the fibrogenic phenotype of PSCs and the underlying molecular mechanism related to FMOD expression in PSCs. Methods We investigated the expression of FMOD in pancreatic tissue and correlation between FMOD expression and fibrosis in patients with CP and the CP rat models. And then, we verified the effects of FMOD was involved in the oxidative stress (OS) by in vitro experiments. Results Drastically higher expression of FMOD was observed in fibrosis tissue of CP patients and rat models compared with controls. Transfection of PSCs with an adenovirus that expressed FMOD increased expression of collagen I (col-I) and α–smooth muscle actin (a-SMA). Up-regulation of FMOD expression promoted proliferation, and migration of PSCs, contributing to their profibrogenic activity. FMOD was sensitive to reactive oxygen species, and its expression increased by incubated with MND. Knockdown FMOD in PSCs abated the α-SMA expression caused by MND. Mechanistically, OS donor increased FMOD production through JNK and ERK signaling pathway. Activator protein-1 bound to the FMOD promoter and transcriptionally regulated FMOD expression in PSCs. Conclusion FMOD levels are up-regulated in fibrosis tissue of CP and is a critical downstream mediator of OS. It could induce PSCs activation and maintain the fibrosis phenotype of PSCs.