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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE305679 | GEO | 2025/12/01

REPOSITORIES: GEO

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