Abstract

Healthy bone possesses intrinsic strength, and strategies aimed at enhancing osteogenesis to improve bone strength are crucial in the treatment of fractures and osteoporosis. Osteocytes, the most abundant cell type in bone tissue, along with the mineralized matrix, form the structural foundation of bone material properties. However, the role of fibroblast growth factor 21 (FGF21) in bone strength, particularly at the level of osteocytes, remains poorly understood and lacks cell-specific evidence. To address this, we generated Dmp1-CreER; Fgf21 fl/fl mice and examined the impact of osteocyte-specific Fgf21 deletion on bone strength. μCT and histological analyses revealed that osteocyte-specific Fgf21 ablation increased both bone formation and resorption in adult mice, resulting in a net anabolic phenotype. Three-point bending demonstrated a significant enhancement in femoral mechanical strength. Moreover, osteocyte Fgf21 deletion accelerated healing in a closed femoral fracture model and reversed ovariectomy-induced bone loss. Transcriptomic profiling, validated at the RNA and protein levels, uncovered activation of Wnt signaling as the underlying mechanism. Collectively, deleting Fgf21 in osteocytes augments the coupling of bone formation and resorption, leading to greater skeletal strength. Targeting osteocytes boosts bone strength and promises new fracture/osteoporosis therapy.