Most organs and tissues in the body, including bone, can repair after an injury due to the activation of endogenous adult stem/progenitor cells to replace the damaged tissue. Inherent dysfunctions of the endogenous stem/progenitor cells in skeletal repair disorders are still poorly understood. Here, we report that Fgfr3^Y637C/+ over-activating mutation in Prx1-derived skeletal stem/progenitor cells leads to failure of fracture consolidation. We show that periosteal cells (PCs) carrying the Fgfr3^Y637C/+ mutation can engage in osteogenic and chondrogenic lineages, but following transplantation do not undergo terminal chondrocyte hypertrophy and transformation into bone causing pseudarthrosis. Instead, Prx1^Cre;Fgfr3^Y637C/+ PCs give rise to fibrocartilage and fibrosis. Conversely, wild-type PCs transplanted at the fracture site of Prx1^Cre;Fgfr3^Y637C/+ mice allow hypertrophic cartilage transition to bone and permit fracture consolidation. The results thus highlight cartilage-to-bone transformation as a necessary step for bone repair and FGFR3 signaling within PCs as a key regulator of this transformation.

由于内源性成年干/祖细胞被激活以替换受损的组织，人体中的大多数器官和组织（包括骨骼）在受伤后都可以修复。骨骼修复疾病中内源性干细胞/祖细胞固有的功能障碍仍然知之甚少。在这里，我们报告在Prx1衍生的骨骼干/祖细胞中Fgfr3 ^{Y637C / +}过度激活突变导致骨折巩固失败。我们显示携带Fgfr3 ^{Y637C / +}突变的骨膜细胞（PCs）可以参与成骨和成软骨谱系，但移植后不会经历终末软骨细胞肥大和转化为骨引起假关节。而是，Prx1 ^Cre ; Fgfr3^{Y637C / +} PC引起纤维软骨和纤维化。相反，移植到Prx1 ^Cre ; Fgfr3 ^{Y637C / +}小鼠骨折部位的野生型PC可以使肥大性软骨过渡到骨骼并允许骨折巩固。因此，结果强调了软骨到骨的转化是PC内骨修复和FGFR3信号转导的必要步骤，是该转化的关键调节因子。