Osteocytic FSH inhibition rescues bone mass and boosts fracture healing in ovariectomized mice
Zemin Liu1, Mingxin Sun2, Hongjie Zhou1
1Department of Orthopaedics, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
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.
Insights
Follicle-stimulating hormone (FSH) directly impacts bone health via osteocytes. Blocking the FSH receptor (FSHR) in these cells enhances bone turnover and accelerates fracture healing, offering new osteoporosis treatment strategies.
Area of Science:
- Bone Biology
- Endocrinology
- Skeletal Physiology
Background:
- Postmenopausal osteoporosis increases fracture risk due to estrogen decline and rising follicle-stimulating hormone (FSH).
- The specific role of circulating FSH in bone loss and its mechanism of action are not fully understood.
- Osteocytes, key regulators of bone homeostasis, are investigated as potential direct targets of FSH.
Purpose of the Study:
- To elucidate the direct function of FSH and its receptor (FSHR) in bone metabolism.
- To investigate the role of osteocyte-mediated mechanisms in FSH's effect on bone.
- To explore the potential of targeting FSHR for osteoporosis treatment.
Main Methods:
- Generated osteocyte-specific Fshr knockout mice (Dmp1-CreERT; Fshrfl/fl).
- Induced Fshr deletion post-ovariectomy using tamoxifen.
- Conducted RNA-sequencing, digital PCR, ELISA, in vitro signaling assays, and biomechanical fracture healing studies.
Main Results:
- Osteocyte-specific Fshr knockout enhanced bone mineralization, resorption, and coupling, activating the PI3K/Akt pathway.
- Fshr deletion in osteocytes blocked FSH-mediated PI3K/Akt inhibition and improved in vitro osteogenic mineralization.
- Knockout mice exhibited accelerated fracture callus maturation and enhanced biomechanical healing.
Conclusions:
- Osteocytes are identified as direct target cells for FSH action.
- Osteocyte Fshr deletion promotes bone turnover and accelerates fracture repair by enhancing PI3K/Akt signaling in ovariectomized mice.
- These findings reveal a novel mechanism in postmenopausal osteoporosis and suggest FSHR as a therapeutic target.
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