The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts.
The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts.
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组蛋白去甲基化酶 KDM5C 通过促进破骨细胞的能量代谢来控制女性骨量。
DOI：
10.1101/2023.02.23.529728
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Krawczyk,ConnieM
中科院分区：
文献类型：
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作者：
Liu,Huadie;Zhai,Lukai;Liu,Ye;Lu,Di;VanderArk,Alexandra;Yang,Tao;Krawczyk,ConnieM
女性患骨质疏松症的比例高于男性。除了荷尔蒙，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去甲基酶KDM5C调节性别特异性骨量。在造血干细胞或骨髓单核细胞中丢失KDM5C会增加雌性小鼠的骨量，但不会增加雄性小鼠的骨量。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。KDM5抑制剂的治疗减少了雌性小鼠和人类单核细胞的破骨细胞生成和能量代谢。我们的报告详细介绍了一种性别相关的骨稳态机制，将表观遗传调节与破骨细胞代谢联系起来，并将KDM5C定位为未来女性骨质疏松症治疗的潜在靶点。
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.