Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model
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Itaru Kawashima1, Masaki Matsushita2, Kenichi Mishima1
1Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 4668550, Nagoya, Aichi, Japan.
Background:
Postmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone regeneration delays fracture healing. Activated fibroblast growth factor receptor 3 (FGFR3) accelerates bone regeneration at juvenile age and downregulates bone mineralization at all ages. However, the impact of FGFR3 signaling on bone regeneration and bone mineralization post-menopause is still unknown. This study aimed to evaluate the impact of FGFR3 signaling on bone regeneration and bone mineralization during menopause by developing a distraction osteogenesis (DO) mouse model after ovariectomy (OVX) using transgenic mice with activated FGFR3 driven by Col2a1 promoter (Fgfr3 mice).
Methods:
The OVX or sham operations were performed in 8-week-old female Fgfr3 and wild-type mice. After 8 weeks of OVX surgery, DO surgery in the lower limb was performed. The 5-day-latency period followed by performing distraction for 9 days. Bone mineral density (BMD) and bone regeneration was assessed by micro-computed tomography (micro-CT) scan and soft X-ray. Bone volume in the distraction area was also evaluated by histological analysis after 7 days at the end of distraction. Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) derived from each mouse after 8 weeks of the OVX or sham operations were also evaluated with and without an inhibitor for FGFR3 signaling (meclozine).
Results:
BMD decreased after OVX in both groups, and it further deteriorated in Fgfr3 mice. Poor callus formation after DO was also observed in both groups with OVX, and the amount of regenerated bone was further decreased in Fgfr3 mice. Similarly, histological analysis revealed that Fgfr3 OVX mice showed lower bone volume. Osteogenic differentiation and mineralization of BMSCs were also deteriorated in Fgfr3 OVX mice. An inhibitor for FGFR3 signaling dramatically reversed the inhibitory effect of OVX and FGFR3 signaling on BMSC mineralization.
Conclusion:
Upregulated FGFR3 decreased newly regenerated bone after DO and BMD in OVX mice. FGFR3 signaling can be a potential therapeutic target in patients with postmenopausal osteoporosis.
Insights
Activated fibroblast growth factor receptor 3 (FGFR3) signaling worsens bone loss and regeneration in postmenopausal osteoporosis. Inhibiting FGFR3 signaling improved bone mineralization, suggesting it as a therapeutic target.
Area of Science:
- Bone Biology
- Endocrinology
- Regenerative Medicine
Background:
- Postmenopausal osteoporosis is a major health issue linked to fracture risk.
- Bone regeneration and mineralization are crucial for fracture healing but are impaired in osteoporosis.
- The role of fibroblast growth factor receptor 3 (FGFR3) signaling in postmenopausal bone health was previously unknown.
Purpose of the Study:
- To investigate the impact of FGFR3 signaling on bone regeneration and mineralization in a mouse model of postmenopausal osteoporosis.
- To develop a distraction osteogenesis (DO) model in ovariectomized (OVX) mice with activated FGFR3.
Main Methods:
- Ovariectomy (OVX) or sham surgery was performed on wild-type and Fgfr3 transgenic mice.
- Distraction osteogenesis (DO) was induced in the lower limb after 8 weeks.
- Bone mineral density (BMD), bone regeneration, and bone volume were assessed using micro-CT, soft X-ray, and histology.
- Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) were evaluated with and without an FGFR3 inhibitor.
Main Results:
- OVX reduced BMD in both groups, with further decline in Fgfr3 mice.
- DO showed poorer callus formation and reduced regenerated bone in OVX mice, especially in Fgfr3 mice.
- FGFR3 signaling exacerbated bone loss and impaired BMSC osteogenic differentiation and mineralization in OVX mice.
- FGFR3 inhibition significantly reversed the negative effects on BMSC mineralization.
Conclusions:
- Upregulated FGFR3 signaling diminishes bone regeneration and BMD in OVX mice.
- FGFR3 signaling represents a potential therapeutic target for treating postmenopausal osteoporosis.
