No abstract

Previous studies examining the role of the histone deacetylase Hdac3 within myeloid cells demonstrated that Hdac3 promotes M2 activation and tissue healing in inflammatory conditions. Since myeloid lineage cells are required for proper bone formation and regeneration, in this study we examined the functions of Hdac3 during bone healing. Conditional deletion of Hdac3 within myeloid progenitors accelerates healing of cortical bone defects. Moreover, reduced osteoclast numbers within the defect site are correlated with Hdac3 suppression. Ex vivo osteoclastogenesis assays further demonstrate that Hdac3 deficiency limits osteoclastogenesis, the number of nuclei per cell and bone resorption, suggesting a defect in cell fusion. High throughput RNA sequencing identified the transmembrane protein Pmepa1 as a differentially expressed gene within osteoclast progenitor cells. Knockdown of Pmepa1 partially restores defects in osteoclastogenesis induced by Hdac3 deficiency. These results show that Hdac3 is required for optimal bone healing and osteoclast fusion, potentially via its regulation of Pmepa1 expression.

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. © 2021 American Society for Bone and Mineral Research (ASBMR).

A reader of the Journal of Bone and Mineral Research (JBMR ® ) has informed the authors that in the article by Weaver et al., (1) the concentration of PTH(7-34) used in vivo was incorrectly stated in the figure legends. The errors are in legends to Figures 3-5, as well as Supplemental Figures 2, 5, and 6. The correct concentration appears in the Materials and Methods section and is 100 μg/kg body weight per day, not 100 mg/kg/day. The cor-

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.