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  • Title: 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.
    Author: Bhatia V, Cao Y, Ko TC, Falzon M.
    Journal: Pancreas; 2016; 45(5):659-70. PubMed ID: 26495794.
    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 (PTHrP) 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). PTHrP 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 PTHrP 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.
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