Gremlin is a key pro-fibrogenic factor in chronic pancreatitis

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2015-10, Vol.93 (10), p.1085-1093
• Main Authors: Staloch, Dustin, Gao, Xuxia, Liu, Ka, Xu, Meihua, Feng, Xueping, Aronson, Judith F., Falzon, Miriam, Greeley, George H., Rastellini, Cristiana, Chao, Celia, Hellmich, Mark R., Cao, Yanna, Ko, Tien C.
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Bone Morphogenetic Protein 2 - antagonists & inhibitors; Bone Morphogenetic Protein 2 - metabolism; Cells, Cultured; Ceruletide; Collagen - metabolism; Female; Fibrosis; Human Genetics; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Internal Medicine; Male; Mice, Transgenic; Molecular Medicine; Original Article; Pancreas - metabolism; Pancreas - pathology; Pancreatic Stellate Cells - metabolism; Pancreatitis, Chronic - chemically induced; Pancreatitis, Chronic - metabolism; Pancreatitis, Chronic - pathology; RNA, Messenger - metabolism; Transforming Growth Factor beta1 - genetics
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-015-1308-9

The current study aims to identify the pro-fibrogenic role of Gremlin, an endogenous antagonist of bone morphogenetic proteins (BMPs) in chronic pancreatitis (CP). CP 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)-β is a known key pro-fibrogenic factor in CP, the TGF-β superfamily member BMPs exert an anti-fibrogenic function in CP as reported by our group recently. To investigate how BMP signaling is regulated in CP by BMP antagonists, the mouse CP model induced by cerulein was used. During CP induction, TGF -β 1 messenger RNA (mRNA) increased 156-fold in 2 weeks, a BMP antagonist Gremlin 1 ( Grem1 ) mRNA levels increased 145-fold at 3 weeks, and increases in Grem1 protein levels correlated with increases in collagen deposition. Increased Grem1 was also observed in human CP pancreata compared to normal. Grem1 knockout in Grem1 +/− mice revealed a 33.2 % reduction in pancreatic fibrosis in CP compared to wild-type littermates. In vitro in isolated pancreatic stellate cells, TGF-β induced Grem1 expression. Addition of the recombinant mouse Grem1 protein blocked BMP2-induced Smad1/5 phosphorylation and abolished BMP2’s suppression effects on TGF-β-induced collagen expression. Evidences presented herein demonstrate that Grem1, induced by TGF-β, is pro-fibrogenic by antagonizing BMP activity in CP. Key messages Gremlin is upregulated in human chronic pancreatitis and a mouse CP model in vivo. Deficiency of Grem1 in mice attenuates pancreatic fibrosis under CP induction in vivo. TGF-β induces Gremlin mRNA and protein expression in pancreatic stellate cells in vitro. Gremlin blocks BMP2 signaling and function in pancreatic stellate cells in vitro. This study discloses a pro-fibrogenic role of Gremlin by antagonizing BMP activity in chronic pancreatitis.