Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Cristiana Rastellini, Song Han, Vandanajay Bhatia, Yanna Cao, Ka Liu, Xuxia Gao, Tien C. Ko, George H. Greeley, Miriam Falzon

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Chronic pancreatitis (CP) is a devastating disease with no treatments. Experimental models have been developed to reproduce the parenchyma and inflammatory responses typical of human CP. For the present study, one objective was to assess and compare the effects of pancreatic duct ligation (PDL) to those of repetitive cerulein (Cer)-induced CP in mice on pancreatic production of bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP). A second objective was to determine the extent of cross talk among pancreatic BMP2, apelin, and PTHrP signaling systems. We focused on BMP2, apelin, and PTHrP since these factors regulate the inflammation-fibrosis cascade during pancreatitis. Findings showed that PDL- and Cer-induced CP resulted in significant elevations in expression and peptide/protein levels of pancreatic BMP2, apelin, and PTHrP. In vivo mouse and in vitro pancreatic cell culture experiments demonstrated that BMP2 stimulated pancreatic apelin expression whereas apelin expression was inhibited by PTHrP exposure. Apelin or BMP2 exposure inhibited PTHrP expression, and PTHrP stimulated upregulation of gremlin, an endogenous inhibitor of BMP2 activity. Transforming growth factor-β (TGF-β) stimulated PTHrP expression. Together, findings demonstrated that PDL- and Cer-induced CP resulted in increased production of the pancreatic BMP2, apelin, and PTHrP signaling systems and that significant cross talk occurred among pancreatic BMP2, apelin, and PTHrP. These results together with previous findings imply that these factors interact via a pancreatic network to regulate the inflammation-fibrosis cascade during CP. More importantly, this network communicated with TGF-β, a key effector of pancreatic pathophysiology. This novel network may be amenable to pharmacologic manipulations during CP in humans.

Original languageEnglish (US)
Pages (from-to)G554-G565
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number7
DOIs
StatePublished - Sep 1 2015

Fingerprint

Parathyroid Hormone-Related Protein
Bone Morphogenetic Protein 2
Pancreatic Ducts
Chronic Pancreatitis
Ligation
Ceruletide
Transforming Growth Factors
Fibrosis
Inflammation
Pancreatitis
Theoretical Models
Up-Regulation
Cell Culture Techniques

Keywords

  • Cross talk
  • Fibrosis
  • Inflammation
  • Interaction
  • Network
  • Signaling

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice. / Rastellini, Cristiana; Han, Song; Bhatia, Vandanajay; Cao, Yanna; Liu, Ka; Gao, Xuxia; Ko, Tien C.; Greeley, George H.; Falzon, Miriam.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 309, No. 7, 01.09.2015, p. G554-G565.

Research output: Contribution to journalArticle

Rastellini, Cristiana ; Han, Song ; Bhatia, Vandanajay ; Cao, Yanna ; Liu, Ka ; Gao, Xuxia ; Ko, Tien C. ; Greeley, George H. ; Falzon, Miriam. / Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2015 ; Vol. 309, No. 7. pp. G554-G565.
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AU - Rastellini, Cristiana

AU - Han, Song

AU - Bhatia, Vandanajay

AU - Cao, Yanna

AU - Liu, Ka

AU - Gao, Xuxia

AU - Ko, Tien C.

AU - Greeley, George H.

AU - Falzon, Miriam

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AB - Chronic pancreatitis (CP) is a devastating disease with no treatments. Experimental models have been developed to reproduce the parenchyma and inflammatory responses typical of human CP. For the present study, one objective was to assess and compare the effects of pancreatic duct ligation (PDL) to those of repetitive cerulein (Cer)-induced CP in mice on pancreatic production of bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP). A second objective was to determine the extent of cross talk among pancreatic BMP2, apelin, and PTHrP signaling systems. We focused on BMP2, apelin, and PTHrP since these factors regulate the inflammation-fibrosis cascade during pancreatitis. Findings showed that PDL- and Cer-induced CP resulted in significant elevations in expression and peptide/protein levels of pancreatic BMP2, apelin, and PTHrP. In vivo mouse and in vitro pancreatic cell culture experiments demonstrated that BMP2 stimulated pancreatic apelin expression whereas apelin expression was inhibited by PTHrP exposure. Apelin or BMP2 exposure inhibited PTHrP expression, and PTHrP stimulated upregulation of gremlin, an endogenous inhibitor of BMP2 activity. Transforming growth factor-β (TGF-β) stimulated PTHrP expression. Together, findings demonstrated that PDL- and Cer-induced CP resulted in increased production of the pancreatic BMP2, apelin, and PTHrP signaling systems and that significant cross talk occurred among pancreatic BMP2, apelin, and PTHrP. These results together with previous findings imply that these factors interact via a pancreatic network to regulate the inflammation-fibrosis cascade during CP. More importantly, this network communicated with TGF-β, a key effector of pancreatic pathophysiology. This novel network may be amenable to pharmacologic manipulations during CP in humans.

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