Parathyroid hormone-related protein interacts with the transforming growth factor-β/bone morphogenetic protein-2/gremlin signaling pathway to regulate proinflammatory and profibrotic mediators in pancreatic acinar and stellate cells

Vandanajay Bhatia, Yanna Cao, Tien C. Ko, Miriam Falzon

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Objectives: Transforming growth factor β (TGF-β) regulates immune and fibrotic responses of chronic pancreatitis. The bone morphogenetic protein 2 (BMP-2) antagonist gremlin is regulated by TGF-β. Parathyroid hormone-related protein (PTHrP) levels are elevated in chronic pancreatitis. Here, we investigated the cross-talk between TGF-β/BMP-2/gremlin and PTHrP signaling. Methods: Reverse transcription/real-time polymerase chain reaction, chromatin immunoprecipitation, Western blotting, and transient transfection were used to investigate PTHrP regulation by TGF-β and BMP-2 and gremlin regulation by PTHrP. The PTHrP antagonist PTHrP (7-34) and acinar cells with conditional Pthrp gene deletion (PTHrPΔacinar) were used to assess PTHrP's role in the proinflammatory and profibrotic effects of TGF-β and gremlin. Results: Transforming growth factor β increased PTHrP levels in acinar cells and pancreatic stellate cells (PSCs) through a Smad3-dependent pathway. Transforming growth factor β's effects on levels of IL-6 and intercellular adhesion molecule 1 (ICAM-1) (acinar cells) and procollagen I and fibronectin (PSCs) were inhibited by PTHrP (7-34). PTHrPΔacinar suppressed TGF-β's effects on IL-6 and ICAM-1. Parathyroid hormone-related hormone increased gremlin in acinar cells, and inhibiting gremlin action suppressed TGF-β's and PTHrP's effects on IL-6 and ICAM-1. Transforming growth factor β-mediated gremlin up-regulation was suppressed in PTHrPΔacinar cells. Bone morphogenetic protein 2 suppressed PTHrP levels in PSCs. Conclusions: Parathyroid hormone-related hormone functions as a novel mediator of the proinflammatory and profibrotic effects of TGF-β. Transforming growth factor β and BMP-2 regulate PTHrP expression, and PTHrP regulates gremlin levels.

Original languageEnglish (US)
Pages (from-to)659-670
Number of pages12
JournalPancreas
Volume45
Issue number5
DOIs
StatePublished - 2016

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Keywords

  • Acinar cells
  • BMP-2
  • Gremlin
  • PTHrP
  • Stellate cells
  • TGF-β

ASJC Scopus subject areas

  • Hepatology
  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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