Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis

Xuxia Gao, Yanna Cao, Dustin A. Staloch, Michael A. Gonzales, Judith Aronson, Celia Chao, Mark Hellmich, Tien C. Ko

Research output: Contribution to journalArticle

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Abstract

Bone morphogenetic proteins (BMPs) have an anti-fibrogenic function in the kidney, lung, and liver. However, their role in chronic pancreatitis (CP) is unknown. The aim of this study was to define the anti-fibrogenic role of BMP signaling in the pancreas in vivo under CP induction. Mice with a deletion of BMP type II receptor (BMPR2+/-) were used in this study in comparison with wild-type mice. CP was induced by repetitive cerulein injection intraperitoneally for 4 weeks, and the severity of CP was evaluated. Pancreatic stellate cells (PSCs) were isolated from the mice and treated with BMP2 and TGF-β in vitro, and extracellular matrix protein (ECM) production was measured. Smad and mitogen-activated protein kinase (MAPK) signaling was also evaluated. BMPR2+/- mice revealed a greater pancreatic fibrosis, PSC activation and leukocyte infiltration after CP induction compared to wild-type mice (P<0.05). Under CP induction, phospho (p)Smad1/5/8 was elevated in wildtype mice and this effect was abolished in BMPR2+/- mice; pSmad2 and pp38MAPK were further enhanced in BMPR2+/- mice compared to wild-type mice (P<0.05). In vitro, BMP2 inhibited TGF-β-induced ECM protein fibronectin production in wild-type PSCs; this effect was abolished in BMPR2+/- PSCs (P<0.05). In BMPR2 +/- PSCs, pSmad1/5/8 level was barely detectable upon BMP2 stimulation, while pSmad2 level was further enhanced by TGF-β stimulation, compared to wild-type PSCs ( P<0.05). BMPR2/Smad1/5/8 signaling plays a protective role against cerulein-induced pancreatic fibrosis by inhibiting Smad2 and p38MAPK signaling pathways.

Original languageEnglish (US)
Article numbere89114
JournalPLoS One
Volume9
Issue number2
DOIs
StatePublished - Feb 21 2014

Fingerprint

Ceruletide
bone morphogenetic proteins
Bone Morphogenetic Proteins
Pancreatic Stellate Cells
fibrosis
Fibrosis
pancreatitis
Chronic Pancreatitis
Extracellular Matrix Proteins
mice
Type II Bone Morphogenetic Protein Receptors
Mitogen-Activated Protein Kinases
Fibronectins
Infiltration
Liver
cells
extracellular matrix
Chemical activation
proteins
fibronectins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. / Gao, Xuxia; Cao, Yanna; Staloch, Dustin A.; Gonzales, Michael A.; Aronson, Judith; Chao, Celia; Hellmich, Mark; Ko, Tien C.

In: PLoS One, Vol. 9, No. 2, e89114, 21.02.2014.

Research output: Contribution to journalArticle

Gao, Xuxia ; Cao, Yanna ; Staloch, Dustin A. ; Gonzales, Michael A. ; Aronson, Judith ; Chao, Celia ; Hellmich, Mark ; Ko, Tien C. / Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. In: PLoS One. 2014 ; Vol. 9, No. 2.
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