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

Objectives: Transforming growth factor beta (TGF-beta) regulates immune and fibrotic responses of chronic pancreatitis. The bone morphogenetic protein 2 (BMP-2) antagonist gremlin is regulated by TGF-beta. Parathyroid hormone-related protein (PTHrP) levels are elevated in chronic pancreatitis. Here, we investigated the cross-talk between TGF-beta/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-beta and BMP-2 and gremlin regulation by PTHrP. The PTHrP antagonist PTHrP (7-34) and acinar cells with conditional Pthrp gene deletion (PTHrP(Delta acinar)) were used to assess PTHrP's role in the proinflammatory and profibrotic effects of TGF-beta and gremlin. Results: Transforming growth factor beta increased PTHrP levels in acinar cells and pancreatic stellate cells (PSCs) through a Smad3-dependent pathway. Transforming growth factor beta'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(Delta acinar) suppressed TGF-beta's effects on IL-6 and ICAM-1. Parathyroid hormone-related hormone increased gremlin in acinar cells, and inhibiting gremlin action suppressed TGF-beta's and PTHrP's effects on IL- 6 and ICAM-1. Transforming growth factor beta-mediated gremlin up-regulation was suppressed in PTHrP(Delta acinar) 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-beta. Transforming growth factor beta and BMP-2 regulate PTHrP expression, and PTHrP regulates gremlin levels.