Fibromodulin is upregulated by oxidative stress through the MAPK/AP-1 pathway to promote pancreatic stellate cell activation.
BACKGROUND/OBJECTIVES
Fibromodulin (FMOD) expression in chronic pancreatitis (CP) tissues and its effect on PSC was unknown. Our aim was to investigate the role of FMOD in regulating PSC profibrogenic phenotype and the molecular mechanism of CP.


METHODS
Rat CP models were induced by dibutyltin dichloride. Pancreatic fibrosis was evaluated by Sirius Red staining. The expression of FMOD and α-SMA was measured, the correlation between FMOD expression and fibrosis was investigated in CP models and CP patients. The effects of FMOD on PSCs were examined by CCK-8 and migration assays. We investigated the mechanisms underlying FMOD expression using MND and a MAPK pathway inhibitor. Luciferase reporter and chromatin immunoprecipitation assays were used to investigate the effects of AP-1 on FMOD expression.


RESULTS
Sirius Red staining revealed high collagen deposition in model rats. Higher expression of FMOD and α-SMA was observed in fibrotic tissues, and the expression of FMOD was correlated with that of α-SMA and the areas of Sirius Red staining. Upregulation of FMOD increased the expression of collagen I and α-SMA and the proliferation and migration of PSCs. MND induced FMOD and α-SMA expression, and knockdown of FMOD abated α-SMA expression. ERK and JNK inhibitors attenuated FMOD expression as induced by MND. AP-1 upregulated the expression of FMOD. AP-1 binds to the FMOD promoter and transcriptionally regulates FMOD expression.


CONCLUSION
FMOD levels are upregulated in fibrosis tissues in CP and it is a critical downstream mediator of oxidative stress. FMOD induces PSC activation and maintains the fibrosis phenotype of PSCs.
['An|Wei|W|', 'Zhu|Jian-Wei|JW|', 'Jiang|Fei|F|', 'Jiang|Hui|H|', 'Zhao|Jiu-Long|JL|', 'Liu|Mu-Yun|MY|', 'Li|Gui-Xiang|GX|', 'Shi|Xin-Gang|XG|', 'Sun|Chang|C|', 'Li|Zhao-Shen|ZS|']
D000199:Actins D000368:Aged D000818:Animals D002478:Cells, Cultured D000071235:Fibromodulin D005355:Fibrosis D006801:Humans D020935:MAP Kinase Signaling System D008297:Male D008875:Middle Aged D018384:Oxidative Stress D058954:Pancreatic Stellate Cells D051381:Rats D017208:Rats, Wistar D015398:Signal Transduction D018808:Transcription Factor AP-1 D015854:Up-Regulation
Fibromodulin Oxidative stress MAPK Pancreatic stellate cells Chronic pancreatitis Activator protein-1