Histone arginine demethylase JMJD7 promotes bone formation through regulating α-Ketoglutarate metabolism

Abstract Histone methylation plays a critical role in chromatin accessibility and transcription regulation, with implications for various disorders, including osteoporosis. Jumonji C domain-containing protein 7 (JMJD7) demethylates arginine (R) residues on histones, influencing tissue metabolism and integrity. However, its role in bone tissue remains uncharacterized. We have discovered JMJD7 loss in human osteoporotic bone biopsies, and neonatal osteoblast-specific Jmjd7 knockout mice exhibit delayed cranial suture closure and premature mortality. Adult female Jmjd7 knockout mice, but not males, develop a smaller stature with hallmark features of osteoporosis and visceral adiposity. Forced Jmjd7 expression mitigates estrogen deficiency-induced bone loss. Jmjd7 deletion alters the transcriptomic landscape and promotes the H3R2me1-enriched epigenome, particularly affecting cellular energy metabolism and suppressing osteogenic differentiation of bone marrow mesenchymal cells. Runx2 is, among others, a functional epigenomic target of Jmjd7. Mechanistically, Jmjd7 loss disrupts energy production by shifting towards anaerobic glycolysis at the expense of mitochondrial oxidative phosphorylation. This metabolic shift is mediated through inhibition of complex I activity and reduced production of isocitrate dehydrogenase (Idh) and its intermediate α-ketoglutarate (α-KG). Notably, α-KG supplementation reverses H3R2me1-dependent transcriptional repression and mitigates post-translational arginine methylation and ubiquitination of Idh and Runx2, counteracting Jmjd7 deletion-induced loss of mineralized matrix synthesis. Furthermore, α-KG supplementation improves osteogenic differentiation and bone formation, attenuating both Jmjd7 loss- and estrogen deficiency-induced osteoporosis. Taken together, Jmjd7 is indispensable for bone integrity, and its loss accelerates osteoporosis through epigenetic repression of α-KG production, affecting mitochondrial energy metabolism and Runx2 signaling. This study reveals a novel anabolic function of Jmjd7 in maintaining bone mass homeostasis and emphasizes the essential role of its cofactor α-KG in promoting bone health.