Gain-of-Function of FGFR3 Accelerates Bone Repair Following Ischemic Osteonecrosis in Juvenile Mice
Gain-of-Function of FGFR3 Accelerates Bone Repair Following Ischemic Osteonecrosis in Juvenile Mice
复制标题
FGFR3 的功能获得加速幼年小鼠缺血性骨坏死后的骨修复
DOI：
10.1007/s00223-022-01019-2
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发表时间：
2022
影响因子：
4.2
通讯作者：
Kitoh Hiroshi
中科院分区：
文献类型：
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作者：
Kato Daisaku;Matsushita Masaki;Takegami Yasuhiko;Mishima Kenichi;Kamiya Nobuhiro;Osawa Yusuke;Imagama Shiro;Kitoh Hiroshi
骨塌陷、骨畸形、疗程长是青少年缺血性骨坏死(Jio)的主要临床问题。加快Jio的骨修复进程有望缩短治疗时间并更好地保持形态。我们先前曾指出，在具有成纤维细胞生长因子受体3(FGFR3)基因功能获得突变的基因工程突变小鼠(即Fgfr3小鼠)中，牵引成骨介导的肢体延长可以加速骨形成和骨吸收。这项研究的目的是研究FGFR3在手术诱导的突变小鼠缺血性骨坏死后的骨修复过程中的作用。在骨骼未成熟年龄的缺血性骨坏死后6周，与野生型小鼠相比，Fgfr3组小鼠的骨骺畸形较少。显微计算机断层扫描(CT)的形态分析显示，Fgfr3组小鼠的骨小梁体积增大。动态骨组织形态计量学显示，术后4周，Fgfr3组小鼠的骨形成率和矿物质沉积增加。Fgfr3小鼠抗酒石酸酸性磷酸酶(TRAP)阳性细胞数迅速增加，TdT介导的dUTP缺口末端标记(TUNEL)阳性细胞数迅速减少。Fgfr3组小鼠术后早期血管内皮生长因子(VEGF)表达增强。FGFR3信号的激活通过加速血管重建、骨吸收和新骨形成，缩短了缺血性骨坏死后骨修复所需的时间。我们的发现具有临床意义，可作为治疗JIO的一种新的潜在策略。
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.,Fgfr3mice). 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 theFgfr3mice 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 theFgfr3mice. Dynamic bone histomorphometry revealed increased rates of bone formation and mineral apposition in theFgfr3mice 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 theFgfr3mice. Vascular endothelial growth factor (VEGF) expression was increased at the earlier phase post-surgery in theFgfr3mice. 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.