2. Academic Validation
  3. Osteocytic FSH inhibition rescues bone mass and boosts fracture healing in ovariectomized mice

Osteocytic FSH inhibition rescues bone mass and boosts fracture healing in ovariectomized mice

  • Life Sci. 2025 Nov 27:385:124121. doi: 10.1016/j.lfs.2025.124121.
Zemin Liu 1,  Mingxin Sun 2,  Hongjie Zhou 1,  Liben Cheng 3,  Xiaoli Li 2,  Bin Chen 1,  Chaoqi Wang 1,  Chao Li 1,  Dong Wang 1,  Yan Li 1,  Juan Li 4,  Yonghong Zhang 5
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
  • 2 School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 3 School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China; Department of Pathology and Physiology, School of Basic Medicine, Peking University, Peking, China.
  • 4 Department of Ultrasound, Second Hospital of Shanxi Medical University, Taiyuan, 030001, China.
  • 5 Department of Orthopaedics, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. Electronic address: [email protected].
PMID: 41317982 DOI: 10.1016/j.lfs.2025.124121
Abstract

Aims: Postmenopausal osteoporosis significantly increases fragility fracture risk. While menopausal estrogen decline coincides with rising follicle-stimulating hormone (FSH), the role of circulating FSH in bone loss remains unclear. This study investigates the direct function of FSH and FSH Receptor (FSHR) in bone, focusing on osteocyte-mediated mechanisms.

Materials and methods: To probe FSHR function, osteocyte-specific Fshr knockout mice (Dmp1-CreERT; Fshrfl/fl) were generated. Following ovariectomy, Fshr deletion was induced with tamoxifen. We performed RNA-sequencing on femoral cortical bone, validated by digital PCR and ELISA. In vitro assays assessed FSH's effect on PI3K/Akt signaling and osteogenic mineralization. Fracture healing and biomechanics were evaluated using a closed femoral fracture model and three-point bending.

Key findings: Osteocyte-specific Fshr knockout enhanced bone mineralization, resorption, and formation-resorption coupling, activating the PI3K/Akt pathway. Fshr deletion blocked FSH-mediated PI3K/Akt inhibition and restored osteogenic mineralization in vitro. Knockout mice showed accelerated callus maturation and improved biomechanical healing post-fracture.

Significance: We identify osteocytes as direct FSH target cells. Osteocyte Fshr deletion promotes bone turnover and accelerates fracture repair in ovariectomized mice by enhancing PI3K/Akt signaling. These findings reveal a new pathophysiological mechanism for postmenopausal osteoporosis and suggest a promising therapeutic strategy targeting FSHR.

Keywords

Bone formation; Bone resorption; Follicle-stimulating hormone; Fracture repair; Ovariectomy; Postmenopausal osteoporosis.

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