TY - JOUR
T1 - Gremlin is a key pro-fibrogenic factor in chronic pancreatitis
AU - Staloch, Dustin
AU - Gao, Xuxia
AU - Liu, Ka
AU - Xu, Meihua
AU - Feng, Xueping
AU - Aronson, Judith F.
AU - Falzon, Miriam
AU - Greeley, George H
AU - Rastellini, Cristiana
AU - Chao, Celia
AU - Hellmich, Mark
AU - Cao, Yanna
AU - Ko, Tien C.
N1 - Funding Information:
The authors thank E. Figueroa, S. Schuenke, and K. Martin in the Department of Surgery, University of Texas Medical Branch for the manuscript and figure preparation and submission. This study was supported by a grant from the National Institutes of Health (P01 DK35608).
Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.
PY - 2015/10/3
Y1 - 2015/10/3
N2 - Abstract: 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-β1 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.
AB - Abstract: 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-β1 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.
KW - Bone morphogenetic protein antagonists
KW - Cerulein
KW - Gremlin
KW - Pancreatic fibrosis
KW - Pancreatic stellate cells
UR - http://www.scopus.com/inward/record.url?scp=84942908124&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84942908124&partnerID=8YFLogxK
U2 - 10.1007/s00109-015-1308-9
DO - 10.1007/s00109-015-1308-9
M3 - Article
C2 - 26141517
AN - SCOPUS:84942908124
SN - 0946-2716
VL - 93
SP - 1085
EP - 1093
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 10
ER -