Laboratory of Skeletal Biology, Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
Department of Metabolism and Nutritional Programming, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Sci Adv. 2023 Apr 5;9(14):eadg0731. doi: 10.1126/sciadv.adg0731.
Women experience osteoporosis at higher rates than men. Aside from hormones, the mechanisms driving sex-dependent bone mass regulation are not well understood. Here, we demonstrate that the X-linked H3K4me2/3 demethylase KDM5C regulates sex-specific bone mass. Loss of KDM5C in hematopoietic stem cells or bone marrow monocytes increases bone mass in female but not male mice. Mechanistically, loss of KDM5C impairs the bioenergetic metabolism, resulting in impaired osteoclastogenesis. Treatment with the KDM5 inhibitor reduces osteoclastogenesis and energy metabolism of both female mice and human monocytes. Our report details a sex-dependent mechanism for bone homeostasis, connecting epigenetic regulation to osteoclast metabolism and positions KDM5C as a potential target for future treatment of osteoporosis in women.
女性骨质疏松的发病率高于男性。除了激素，驱动性别依赖性骨量调节的机制还不是很清楚。在这里，我们证明了 X 连锁的 H3K4me2/3 去甲基化酶 KDM5C 调节性别特异性骨量。造血干细胞或骨髓单核细胞中 KDM5C 的缺失增加了雌性而非雄性小鼠的骨量。从机制上讲，KDM5C 的缺失会损害生物能量代谢，导致破骨细胞生成受损。用 KDM5 抑制剂治疗可减少雌性小鼠和人单核细胞的破骨细胞生成和能量代谢。我们的报告详细描述了一个性别依赖的骨稳态机制，将表观遗传调控与破骨细胞代谢联系起来，并将 KDM5C 作为未来女性骨质疏松治疗的潜在靶点。
