陆军军医大学学报2026，Vol.48Issue(12)：1648-1666,19.DOI:10.16016/j.2097-0927.202603027
成纤维细胞生长因子7通过激活FGFR1通路促进骨关节炎滑膜纤维化
Fibroblast growth factor 7 promotes synovial fibrosis in osteoarthritis by activating the FGFR1 signaling pathway
摘要
Abstract
Objective Synovial fibrosis is an important pathological change in osteoarthritis(OA)and is closely associated with disease progression.During the progression of synovial fibrosis in OA,fibroblasts differentiate into myofibroblasts,leading to abnormal deposition of extracellular matrix(ECM)and resulting in clinical symptoms such as joint pain and limited mobility.This study aims to investigate the role and cellular and molecular mechanisms of the fibroblast growth factor 7(FGF7)-fibroblast growth factor receptor 1(FGFR1)signaling axis in OA synovial fibrosis.Methods ① By mining publicly available synovial single-cell sequencing data,combined with differential analysis,enrichment analysis,fibrosis scoring,correlation analysis,and virtual knockout techniques,the relationship between FGF7/FGFR1 and OA synovial fibrosis was explored.② An OA mouse model was established via destabilization of the medial meniscus(DMM),and the mice receiving sham surgery served as the control group.Recombinant FGF7 protein(2 μg/10 μL)or PBS was injected into the joint cavity once weekly for 4 weeks.Functional assessments were performed at 4(n=6)and 8 weeks(n=5)after modeling via behavioral testing,including gait analysis,hindlimb balance test,and knee joint range-of-motion evaluation.Histopathological analyses,including HE,Masson's trichrome,and Sirius Red staining,as well as immunostaining for collagen type Ⅰ alpha 1 chain(COL1A1)and alpha-smooth muscle actin(α-SMA),were conducted to evaluate synovial fibrosis and inflammatory changes.③ EdU,CCK-8 assay,wound-healing assay,qPCR,and Western blotting were applied to investigate the role of FGF7 in fibroblast-to-myofibroblast differentiation.Results ① FGF7 expression was positively correlated with synovial fibrosis scores.② Exogenous FGF7 markedly aggravated OA-related joint dysfunction in DMM mice.At 4 weeks post-DMM,compared with the PBS group,the FGF7 group showed decreased distribution of right hindlimb ground contact time(P<0.01),right hindlimb weight-bearing(P<0.01),and knee joint range-of-motion(P<0.001),with a similar trend observed at 8 weeks post-DMM.③ FGF7 promoted ECM deposition and upregulated fibrosis markers in the synovial tissues.Histological analysis revealed that FGF7 treatment significantly aggravated synovial inflammation at 4 weeks(P<0.000 1)and 8 weeks(P<0.01),and promoted ECM deposition compared with the PBS group.COL1A1 immunohistochemical staining indicated increased type Ⅰ collagen deposition in the FGF7 group at 4(P<0.05)and 8 weeks(P<0.000 1),and immunofluorescence assay showed increased α-SMA expression in the FGF7 group at 4(P<0.001)and 8 weeks(P<0.01).④ In in vitro study,EdU and CCK-8 assays indicated that FGF7 promoted fibroblast proliferation(P<0.05);the scratch assay showed that FGF7 enhanced fibroblast migration(P<0.01);FGF7 upregulated α-SMA(P<0.001)and COL1A1(P<0.001)expression in fibroblasts.⑤Mechanistically,FGF7 exerted pro-fibrotic effects through the FGFR1 pathway.FGF7 activated p-FGFR1(P<0.05)and p-ERK(P<0.01)expression in fibroblasts;BGJ398 inhibited the FGF7-induced upregulation of p-FGFR1(P<0.05),p-ERK(P<0.05),COL1A1(P<0.05),and α-SMA(P<0.01)in fibroblasts.Conclusion Exogenous FGF7 exacerbates synovial fibrosis in OA mice.Our findings revealed that FGF7 promotes fibroblast proliferation,migration,and differentiation into myofibroblasts via activation of the FGFR1 pathway,thereby providing a potential novel target for the treatment of OA synovial fibrosis.关键词
FGF7/FGFR1/骨关节炎/滑膜纤维化Key words
FGF7/FGFR1/osteoarthritis/synovial fibrosis分类
医药卫生引用本文复制引用
刘人豪,陈亮,旷梁,陈林,杨俊,李孝红,韩佳洺,彭秀琴,王海霖,雷庆强,毛雪芹,田雨..成纤维细胞生长因子7通过激活FGFR1通路促进骨关节炎滑膜纤维化[J].陆军军医大学学报,2026,48(12):1648-1666,19.基金项目
科技部重点研发计划子课题(2022YFA1103202) （2022YFA1103202）
国家自然科学基金重大项目(82394444) （82394444）
国家自然科学基金面上项目(82272559) （82272559）
重庆市自然科学基金重点项目(CSTB2024NSCQ-LZX0104) （CSTB2024NSCQ-LZX0104）
重庆市科卫联合医学科研项目(2024DBXM008). Supported by the Sub-Project of National Key Research and Development Program of China(2022YFA1103202),the Major Project of National Natural Science Foundation of China(82394444),the General Project of National Natural Science Foundation of China(82272559),the Key Project of Natural Science Foundation of Chongqing(CSTB2024NSCQ-LZX0104),and the Joint Medical Research Project of Chongqing Science and Technology Commission and Chongqing Health Commission(2024DBXM008). （2024DBXM008）
