Department of Orthopedics, University of Minnesota, Elizabeth W. Bradley, 100 Church St. S.E., Minneapolis, MN, 55455, USA.
Departments of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
Sci Rep. 2020 Dec 11;10(1):21804. doi: 10.1038/s41598-020-78364-5.
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.
先前的研究表明，组蛋白去乙酰化酶 Hdac3 在髓系细胞中发挥作用，促进炎症条件下的 M2 激活和组织修复。由于髓系细胞对正常骨形成和再生至关重要，因此在这项研究中，我们研究了 Hdac3 在骨愈合过程中的功能。在髓系前体细胞中条件性缺失 Hdac3 可加速皮质骨缺损的愈合。此外，缺陷部位破骨细胞数量减少与 Hdac3 抑制相关。体外破骨细胞生成实验进一步表明，Hdac3 缺乏限制破骨细胞生成、每个细胞的细胞核数量和骨吸收，表明细胞融合缺陷。高通量 RNA 测序鉴定出跨膜蛋白 Pmepa1 是破骨细胞前体细胞中差异表达的基因。Pmepa1 的敲低部分恢复了由 Hdac3 缺乏引起的破骨细胞生成缺陷。这些结果表明，Hdac3 是骨愈合和破骨细胞融合的必要条件，可能通过其对 Pmepa1 表达的调节。
