Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Department of Sports Medicine, Tenri University, 80 Tainosho-cho, Tenri, 632-0071, Japan.
Calcif Tissue Int. 2022 Dec;111(6):622-633. doi: 10.1007/s00223-022-01019-2. Epub 2022 Sep 7.
Bone collapse, bone deformity, and a long treatment period are major clinical problems associated with juvenile ischemic osteonecrosis (JIO). Accelerating the process of bone repair in JIO is expected to shorten the treatment duration and better maintain morphology. We previously indicated that both bone formation and resorption were accelerated following distraction osteogenesis-mediated limb lengthening in genetically engineered mutant mice with a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3) gene (i.e., Fgfr3 mice). The purpose of this study was to investigate the role of FGFR3 in the bone repair process following surgically induced ischemic osteonecrosis in the mutant mice. Epiphyseal deformity was less in the Fgfr3 mice compared to the wild-type mice at 6 weeks following ischemic osteonecrosis in skeletally immature age. Assessment of the morphology by micro-computed tomography (CT) revealed that the trabecular bone volume was increased in the Fgfr3 mice. Dynamic bone histomorphometry revealed increased rates of bone formation and mineral apposition in the Fgfr3 mice at 4 weeks post-surgery. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells rapidly increased, and the numbers of TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells rapidly decreased in the Fgfr3 mice. Vascular endothelial growth factor (VEGF) expression was increased at the earlier phase post-surgery in the Fgfr3 mice. The activation of FGFR3 signaling shortens the time needed for bone repair after ischemic osteonecrosis by accelerating revascularization, bone resorption, and new bone formation. Our findings are clinically relevant as a new potential strategy for the treatment of JIO.
骨塌陷、骨畸形和治疗周期长是青少年缺血性骨坏死（JIO）的主要临床问题。加速 JIO 中的骨修复过程有望缩短治疗时间并更好地维持形态。我们之前表明，在具有成纤维细胞生长因子受体 3（FGFR3）基因功能获得性突变的基因工程突变小鼠中，通过牵张成骨介导的肢体延长后，骨形成和吸收均加速（即 Fgfr3 小鼠）。本研究旨在研究 FGFR3 在突变小鼠手术诱导的缺血性骨坏死后骨修复过程中的作用。与野生型小鼠相比，在骨骼未成熟年龄发生缺血性骨坏死 6 周后，Fgfr3 小鼠的骺板畸形程度较轻。通过微计算机断层扫描（CT）评估形态学，发现 Fgfr3 小鼠的小梁骨体积增加。动态骨组织形态计量学显示，Fgfr3 小鼠在手术后 4 周时骨形成和矿化附着率增加。抗酒石酸酸性磷酸酶（TRAP）阳性细胞数量迅速增加，Fgfr3 小鼠的 TdT 介导的 dUTP 缺口末端标记（TUNEL）阳性细胞数量迅速减少。Fgfr3 小鼠术后早期血管内皮生长因子（VEGF）表达增加。FGFR3 信号的激活通过加速再血管化、骨吸收和新骨形成，缩短缺血性骨坏死后骨修复所需的时间。我们的发现具有临床相关性，是治疗 JIO 的一种新的潜在策略。
