title: Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis.
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 wild-type mice and this effect was abolished in BMPR2(+/-) mice; pSmad2 and pp38(MAPK) 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 p38(MAPK) signaling pathways.
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America ; Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Staloch
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzales
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Judith F
authors.initials: JF
authors.lastname: Aronson
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Celia
authors.initials: C
authors.lastname: Chao
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellmich
authors.affiliation: Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America ; Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Tien C
authors.initials: TC
authors.lastname: Ko
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002108:Ceruletide; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010182:Pancreatic Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019485:Bone Morphogenetic Proteins; D002108:Ceruletide; D052006:Bone Morphogenetic Protein Receptors, Type II