Setd7 orchestrates mitochondrial fusion to drive site-specific osteogenic homeostasis and alleviate osteoporosis

Setd7 mediates crosstalk between epigenetic and metabolic signaling to regulate lineage-specific and site-specific bone homeostasis. Osteoporosis stems from impaired osteogenic activity and skeletal compartmental imbalance, and the mechanisms that coordinately regulate craniofacial and appendicular bone remain elusive. Here, we demonstrate that Setd7 epigenetically promotes mitochondrial fusion to drive osteogenic commitment of bone marrow mesenchymal stem cells for appendicular bone development, while enhancing the osteogenic capacity of osteoprogenitors to support craniofacial bone formation. Conditional knockout of Setd7 in mesenchymal stem cells significantly reduced femoral bone mineral density, along with impaired somatic growth and body weight. In contrast, Setd7 deletion in osteoprogenitors specifically impaired craniofacial bone mass, revealing that Setd7 exerts distinct cell type-dependent regulatory effects on skeletal compartmentalization. Mechanistically, Setd7 epigenetically orchestrates mitochondrial fusion in both bone marrow mesenchymal stem cells and osteoprogenitors, as evidenced by increased mitochondrial membrane potential, decreased reactive oxygen species production, and elevated ATP generation. This mitochondrial reprogramming enhances cellular bioenergetics and redox homeostasis, which in turn amplifies osteogenic differentiation and bone matrix mineralization. Together, these findings define the Setd7-mitochondrial fusion cascade as an epigenetic-metabolic signaling module that controls site-specific osteogenic homeostasis, thereby identifying Setd7 as a target to alleviate osteoporotic bone loss by balancing mitochondrial dynamics and histone methylation. Histone methyltransferase Setd7 coordinates mitochondrial fusion to sustain site-specific osteogenic homeostasis and relieve osteoporosis. In BMSCs and osteoprogenitors, Setd7 boosts mitochondrial fusion to raise ATP levels, lower ROS, and facilitate osteogenic differentiation, with osteoprogenitor ablation impairing craniofacial bone and mesenchymal deletion damaging femoral appendicular bone