Conditional Knockout of Fshr in Osteocytes Restores Bone Mass and Accelerates Fracture Healing in Ovariectomized Mice

Building on our previous observation that osteocytes express FSH receptors (FSHR), we generated Dmp1-CreERT; Fshrfl/fl mice and subjected them to ovariectomy (OVX), followed by weekly tamoxifen administration to achieve osteocyte-specific Fshr deletion. Osteocyte-specific Fshr knockout mice exhibited increased bone mineralization alongside elevated bone resorption. RNA-seq of femoral cortical bone revealed enhanced coupling of bone formation and resorption, which was associated with PI3K/Akt pathway activation. Digital PCR and ELISA confirmed up-regulation of osteoblast- and osteoclast-related genes. In vitro, Fshr deletion abolished FSH-mediated inhibition of the PI3K/Akt pathway and restored osteogenic mineralization of bone-marrow mesenchymal stem cells (BMSCs). In a closed femoral-fracture model, osteocyte-specific Fshr knockout accelerated callus maturation and fracture healing, and three-point bending tests demonstrated improved biomechanical properties. These findings identify osteocytes as direct FSH-responsive cells within bone. Osteocyte-specific Fshr deletion enhances PI3K/Akt signaling, enhancing formation–resorption coupling, and accelerates fracture repair in ovariectomized mice. Our study provides mechanistic insights and potential therapeutic strategies for postmenopausal osteoporosis and fracture management. Overall design: In the study, femur samples were collected from three mice in the tamoxifen - induced FGF21 knockout group (A1-A3) and three mice in the corn oil - injected control group (B1-B3) for subsequent RNA extraction and high - throughput sequencing procedures.