Gremlin is a key pro-fibrogenic factor in chronic pancreatitis

Dustin Staloch, Xuxia Gao, Ka Liu, Meihua Xu, Xueping Feng, Judith Aronson, Miriam Falzon, George H. Greeley, Cristiana Rastellini, Celia Chao, Mark Hellmich, Yanna Cao, Tien C. Ko

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1085-1093
Number of pages9
JournalJournal of Molecular Medicine
Volume93
Issue number10
DOIs
StatePublished - Oct 3 2015

Fingerprint

Chronic Pancreatitis
Bone Morphogenetic Proteins
Transforming Growth Factors
Pancreatic Stellate Cells
Fibrosis
Messenger RNA
Collagen
Ceruletide
Pancreas
Proteins

Keywords

  • Bone morphogenetic protein antagonists
  • Cerulein
  • Gremlin
  • Pancreatic fibrosis
  • Pancreatic stellate cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Gremlin is a key pro-fibrogenic factor in chronic pancreatitis. / Staloch, Dustin; Gao, Xuxia; Liu, Ka; Xu, Meihua; Feng, Xueping; Aronson, Judith; Falzon, Miriam; Greeley, George H.; Rastellini, Cristiana; Chao, Celia; Hellmich, Mark; Cao, Yanna; Ko, Tien C.

In: Journal of Molecular Medicine, Vol. 93, No. 10, 03.10.2015, p. 1085-1093.

Research output: Contribution to journalArticle

Staloch, D, Gao, X, Liu, K, Xu, M, Feng, X, Aronson, J, Falzon, M, Greeley, GH, Rastellini, C, Chao, C, Hellmich, M, Cao, Y & Ko, TC 2015, 'Gremlin is a key pro-fibrogenic factor in chronic pancreatitis', Journal of Molecular Medicine, vol. 93, no. 10, pp. 1085-1093. https://doi.org/10.1007/s00109-015-1308-9
Staloch, Dustin ; Gao, Xuxia ; Liu, Ka ; Xu, Meihua ; Feng, Xueping ; Aronson, Judith ; Falzon, Miriam ; Greeley, George H. ; Rastellini, Cristiana ; Chao, Celia ; Hellmich, Mark ; Cao, Yanna ; Ko, Tien C. / Gremlin is a key pro-fibrogenic factor in chronic pancreatitis. In: Journal of Molecular Medicine. 2015 ; Vol. 93, No. 10. pp. 1085-1093.
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abstract = "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.",
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AU - Staloch, Dustin

AU - Gao, Xuxia

AU - Liu, Ka

AU - Xu, Meihua

AU - Feng, Xueping

AU - Aronson, Judith

AU - Falzon, Miriam

AU - Greeley, George H.

AU - Rastellini, Cristiana

AU - Chao, Celia

AU - Hellmich, Mark

AU - Cao, Yanna

AU - Ko, Tien C.

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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.

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KW - Pancreatic stellate cells

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