Department of Pediatric Dentistry, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Bone. 2022 Jun;159:116379. doi: 10.1016/j.bone.2022.116379. Epub 2022 Mar 16.
Osteoclasts are the principal bone resorption cells crucial for homeostatic bone remodeling and pathological bone destruction. Increasing data demonstrate a vital role of histone methylation in osteoclastogenesis. As an integral core subunit of H3K4 methyltransferases, Dpy30 is notal as a key chromatin regulator for cell growth and differentiation and stem cell fate determination, particularly in the hematopoietic system. However, its role in osteoclastogenesis is currently unknown. Herein, we generated Dpy30; LysM-Cre mice, which deletes Dpy30 in myeloid cells, to characterize its involvement in osteoclast differentiation and function. Dpy30; LysM-Cre mice showed increased bone mass, evident by impaired osteoclastogenesis and defective osteoclast activity, but no alteration of osteoblast numbers and bone formation. Additionally, our ex vivo analysis showed that the loss of Dpy30 significantly impedes osteoclast differentiation and suppresses osteoclast-related gene expression. Moreover, Dpy30 deficiency significantly decreased the enrichment of H3K4me3 on the promoter region of NFATc1. Thus, we revealed a novel role for Dpy30 in osteoclastogenesis through epigenetic mechanisms, and that it could potentially be a therapeutic target for bone destruction diseases.
破骨细胞是主要的骨吸收细胞，对于维持骨重塑和病理性骨破坏至关重要。越来越多的数据表明组蛋白甲基化在破骨细胞发生中起着重要作用。作为 H3K4 甲基转移酶的一个整合核心亚基，Dpy30 作为细胞生长和分化以及干细胞命运决定的关键染色质调节剂而备受关注，特别是在造血系统中。然而，其在破骨细胞发生中的作用目前尚不清楚。在此，我们构建了 Dpy30; LysM-Cre 小鼠，该小鼠在髓系细胞中缺失 Dpy30，以研究其在破骨细胞分化和功能中的作用。Dpy30; LysM-Cre 小鼠表现出骨量增加，这可通过破骨细胞发生受损和破骨细胞活性缺陷来证明，但成骨细胞数量和骨形成没有改变。此外，我们的体外分析表明，Dpy30 的缺失显著阻碍了破骨细胞的分化，并抑制了破骨细胞相关基因的表达。此外，Dpy30 缺乏显著降低了 NFATc1 启动子区域上 H3K4me3 的富集。因此，我们通过表观遗传机制揭示了 Dpy30 在破骨细胞发生中的新作用，并且它可能成为骨破坏疾病的治疗靶点。
