title: Gremlin is a key pro-fibrogenic factor in chronic pancreatitis.
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.
  
  
  CONCLUSIONS
  • 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.
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Texas.
authors.forename: Dustin
authors.initials: D
authors.lastname: Staloch
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Texas.|Department of General Practice, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Texas.
authors.forename: Ka
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Texas.|Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Texas.|Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Judith F
authors.initials: JF
authors.lastname: Aronson
authors.affiliation: Department of Pharmacology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Miriam
authors.initials: M
authors.lastname: Falzon
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
authors.forename: George H
authors.initials: GH
authors.lastname: Greeley
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Rastellini
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Celia
authors.initials: C
authors.lastname: Chao
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellmich
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Texas.|Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Texas.|Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Tien C
authors.initials: TC
authors.lastname: Ko
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D002108:Ceruletide; D003094:Collagen / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D016207:Cytokines
chemical_list: D055396:Bone Morphogenetic Protein 2; D002108:Ceruletide; D003094:Collagen; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C525719:Bmp2 protein, mouse; C486399:GREM1 protein, human; C113178:Grem1 protein, mouse; D016207:Cytokines
keywords: Bone morphogenetic protein antagonists; Cerulein; Gremlin; Pancreatic fibrosis; Pancreatic stellate cells