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.

中文翻译：

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FGFR3缺乏通过上调CXCR7增强巨噬细胞CXCL12依赖性趋化性并加重小鼠关节破坏

目的 本研究旨在探讨 FGFR3 在巨噬细胞中的作用和机制及其对关节炎病理学的生物学影响。方法 产生条件性敲除骨髓细胞中 FGFR3 (R3cKO) 的小鼠。在不同年龄监测小鼠的步态行为。通过数字放射成像和 μCT 分析评估自发性滑膜关节破坏；通过组织学分析确定关节软骨和滑膜炎的变化。通过免疫染色和单核细胞运输测定检查滑膜中巨噬细胞的募集。对对照和 FGFR3 缺陷巨噬细胞进行 RNA-seq 分析、蛋白质印迹和趋化性实验。分析了来自非骨关节炎 (OA) 捐献者和 OA 患者的外周血。用针对 CXCR7 的中和抗体处理小鼠以研究 CXCR7 在关节炎中的作用。结果 R3cKO 小鼠而非对照小鼠在 13 个月大时在多个滑膜关节中发生自发性软骨破坏。此外，当关节软骨未受到严重破坏时，在 9 个月大的 R3cKO 小鼠的关节中观察到滑膜炎和巨噬细胞积聚。骨髓细胞中的 FGFR3 缺陷也加剧了 DMM 小鼠模型中的关节破坏。从机制上讲，FGFR3 缺乏部分通过激活 NF-κB/CXCR7 通路促进巨噬细胞趋化。抑制 CXCR7 可以显着逆转 FGFR3 缺陷增强的巨噬细胞趋化性和 R3cKO 小鼠的关节炎表型。结论 我们的研究确定了 FGFR3 在滑膜巨噬细胞募集和滑膜炎中的作用，