Complement factor H (CFH), an immune factor enhances osteoblast differentiation and correlates with bone density.

Complement factor H (CFH) is an immune regulator that inhibits the complement system. Here, we identify CFH as a secreted and regulated factor in human bone marrow skeletal stem cells (hBMSCs) culture during osteoblast (OB) differentiation. To explore its role in bone formation, we investigated the effects of CFH on OB differentiation and bone homeostasis. CFH-deficient hBMSCs exhibited impaired OB differentiation, whereas CFH overexpression or supplementation enhanced OB differentiation in hBMSCs. In vivo, CFH-deficient (CFH-/-) mice displayed reduced trabecular and cortical bone mass, decreased bone formation, and diminished bone strength. Primary CFH-/- mouse bone marrow MSCs (mBMSCs) showed reduced osteogenesis but enhanced osteoclast differentiation, consistent with lower serum levels of the bone formation marker P1NP and elevated bone resorption markers TRAPc and CTX-1. Furthermore, CFH-/- mice exhibited delayed fracture healing and accelerated bone loss following ovariectomy or high-fat diet feeding. Clinically, CFH levels in bone marrow plasma were negatively correlated with fracture risk in patients. Notably, plasma CFH levels were positively associated with bone mineral density (BMD) and were significantly reduced in patients with osteoporosis. These findings establish CFH as a key regulator of osteogenesis and bone homeostasis, with potential implications for bone-related disorders.