Chen Hao, Cui Yujia, Li Jiazhou, Duan Mengmeng, Pi Caixia, Zhou Xuedong, Xie Jing
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Int J Biol Sci. 2025 Jul 4;21(10):4428-4449. doi: 10.7150/ijbs.110133. eCollection 2025.
Fibroblast growth factor 19 (FGF19) has received increasing attention in metabolic disorders of the skeletal system, but its role in cartilage development is poorly understood. In the present study, we used metatarsal organ model for nascent cartilage and an AAV-FGF19 overexpression model for adolescent growth plates to demonstrate the influence of FGF19 on cartilage development. We found that FGF19 could impair chondrocyte maturation at the neonatal stage and decrease growth plate thickness at the adolescent stage. FGF19 reduces chondrogenic differentiation of mesenchymal stem cells and the chondrocyte maturation via downregulation of Wnt/β-catenin signalling. FGF19-mediated chondrocyte maturation and cartilage differentiation require the participation of FGFR4 with the aid of β-klotho (KLB). FGF19 signalling entered the cytoplasm through FGFR4, activated the expression of SFRP1, WIF1 and DKK2, which are antagonists of β-catenin signalling, and hindered chondrocyte proliferation and cartilage growth. This study demonstrates for the first time that FGF19 inhibits cartilage development through the FGFR4/β-catenin axis, providing evidence for the vital role of FGF19 in growth plate chondrogenesis and endochondral ossification.
成纤维细胞生长因子19（FGF19）在骨骼系统的代谢紊乱中受到越来越多的关注，但其在软骨发育中的作用却鲜为人知。在本研究中，我们使用新生软骨的跖骨器官模型和青少年生长板的AAV-FGF19过表达模型来证明FGF19对软骨发育的影响。我们发现，FGF19可在新生儿期损害软骨细胞成熟，并在青少年期降低生长板厚度。FGF19通过下调Wnt/β-连环蛋白信号通路减少间充质干细胞的软骨形成分化和软骨细胞成熟。FGF19介导的软骨细胞成熟和软骨分化需要FGFR4在β-klotho（KLB）的帮助下参与。FGF19信号通过FGFR4进入细胞质，激活β-连环蛋白信号通路拮抗剂SFRP1、WIF1和DKK2的表达，从而阻碍软骨细胞增殖和软骨生长。本研究首次证明FGF19通过FGFR4/β-连环蛋白轴抑制软骨发育，为FGF19在生长板软骨形成和软骨内骨化中的重要作用提供了证据。
