The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts.

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.