Gremlin is a key pro-fibrogenic factor in chronic pancreatitis

The current study aims to identify the pro-fibrogenic role of Gremlin, an endogenous antagonist of bone morphogenctic proteins (BMPs) in chronic pancreatitis (CP). CF is a highly debilitating disease characterized by progressive pancreatic inflammation and fibrosis that ultimately leads to exocrine and endocrine dysfunction. While transforming growth factor (TGF)-(3 is a known key pro-fibrogenic factor in CP, the TGF-(3 superfamily member BMPs exert an anti-fibrogcnic function in CP as reported by our group recently. To investigate how BMP signaling is regulated in CP by BMP antagonists, the mouse CF model induced by cerulein was used. During CP induction, TGF-1 3 1 messenger RNA (mRNA) increased 156-fold in 2 weeks, a BMP antagonist Gremlin 1 (Greml) mRNA levels increased 145fold at 3 weeks, and increases in Greml protein levels correlated with increases in collagen deposition. Increased Grem 1 was also observed in human CP pancrcata compared to normal, Grem 1 knockout in Gremr- mice revealed a 33,2 % reduction in pancreatic fibrosis in CF compared to wild-type littermates. In vitro in isolated pancreatic stellate cells, TGF-13 induced Greml expression. Addition of the recombinant mouse Greml protein blocked BMP2-induced Smad1/5 phosphorylation and abolished BMP2's suppression effects on TGF-13-induced collagen expression. Evidences presented herein demonstrate that Greml, induced by TGF-13, is pro-fibrogenic by antagonizing BMP activity in CP.