Objectives This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis.
Methods Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis.
Results R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice.
Conclusions Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.
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Handling editor Josef S Smolen
Contributors LK conducted the majority of the experiments and completed the manuscript. JW participated in the experiment and helped with manuscript preparation. HQ, NS, XD and DC improved the manuscript. HC, WJ and QT helped with animal housing and genotype identification. JO and BZ collected animal samples and scoring. SZ, YXio, LiaC, SC, ZuqW, ZimW and PL collected human samples. JY, MJ, FL and LY did the micro-CT scanning. FG, CD and CL revised the manuscript. LinC, ZN and YXie developed the concept, supervised the project, conceived the experiments, analysed the data and critically reviewed the manuscript.
Funding This work was supported by National Key Research and Development Program of China (2018YFA0800802); National Natural Science Foundation of China (No. 81530071; No. 31571382; No. 81871817); the Key Project of Innovation Program in Military Medicine (16CXZ016); National Postdoctoral Program for Innovative Talents (BX201600023); Project of the State Key Laboratory of Trauma, Burns and Combined Injury (No. SKLZZ(III)201601).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Human study was approved by the Ethical and Protocol Review Committee of Daping Hospital. All animal experiments were approved by the Institutional Animal Care and Use Committee of Daping Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information.