Endochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 (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 PTH receptor 1 (Pth1r) expression and enrichment of histone 3 lysine 27 acetylation (H3K27ac) at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH (1-34) enhanced and PTH (7-34) attenuated cell proliferation, cAMP signaling, cAMP response element-binding protein (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 4 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 show 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.
Bibliographical noteFunding Information:
This work was supported by research and training grants from the National Institute of Arthritis Musculoskeletal and Skin Diseases (AR) and the National Institute of Diabetes and Digestive and Kindey Dieases (AR068103 (JJW), AR056950 (JJW, ELT), DK07352 (SRW), AR065397 (EWB), AR072634 (EWB)). We thank Xiaodong Li and Carys Turner for technical assistance. The Mayo Clinic X‐Ray Imaging Resources Core Facilities were essential for collection of the μCT data. We are grateful to the Mayo Clinic Medical Genome Facility Sequencing Core for performing and helping with the analysis of ChIP‐Sequencing.
- CHONDROCYTE AND CARTILAGE BIOLOGY
- GROWTH PLATE
- MOLECULAR PATHWAYS – DEVELOPMENT
- PTH/VIT D/FGF23
PubMed: MeSH publication types
- Journal Article