TY - JOUR T1 - PH domain and leucine rich repeat phosphatase 1 (Phlpp1) suppresses parathyroid hormone receptor 1 (Pth1r) expression and signaling during bone growth JF - bioRxiv DO - 10.1101/2020.12.06.413567 SP - 2020.12.06.413567 AU - Samantha R. Weaver AU - Earnest L. Taylor AU - Elizabeth L. Zars AU - Katherine M. Arnold AU - Elizabeth W. Bradley AU - Jennifer J. Westendorf Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/12/06/2020.12.06.413567.abstract N2 - Endochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). PH domain and leucine rich repeat phosphatase (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1−/− mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater Pth1r expression and H3K27ac enrichment at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH(1-34) enhanced and PTH(7-34) attenuated cell proliferation, cAMP signaling, CREB phosphorylation, and cell metabolic activity in Phlpp1-inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1-deficient mice, Phlpp1−/− mice were injected with Pth1r ligand PTH(7-34) daily for the first four weeks of life. PTH(7-34) reversed the abnormal growth plate and long bone growth phenotypes of Phlpp1−/− mice but did not rescue deficits in bone mineral density or trabecular number. These results demonstrate that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1−/− chondrocytes and shorter bones in Phlpp1-deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth.Competing Interest StatementThe authors have declared no competing interest. ER -