Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
Center for Joint Surgery, Southwest Hospital, Army Medical University, Chongqing, China.
Ann Rheum Dis. 2020 Jan;79(1):112-122. doi: 10.1136/annrheumdis-2019-215696. Epub 2019 Oct 29.
This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis.
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.
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.
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.
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的生物学影响。
构建骨髓细胞条件性敲除 FGFR3（R3cKO）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迁移测定检查滑膜中巨噬细胞的募集。对对照和 FGFR3 缺陷型巨噬细胞进行 RNA-seq 分析、Western blot 分析和趋化实验。分析非骨关节炎（OA）供体和 OA 患者的外周血。用 CXCR7 中和抗体治疗小鼠，以研究 CXCR7 在关节炎中的作用。
R3cKO 小鼠但不是对照小鼠在 13 月龄时自发地在多个滑膜关节中发生软骨破坏。此外，在关节软骨未明显破坏时，9 月龄的 R3cKO 小鼠的关节中也观察到滑膜炎和巨噬细胞聚集。骨髓细胞中 FGFR3 的缺失也加重了 DMM 小鼠模型中的关节破坏。在机制上，FGFR3 缺失部分通过激活 NF-κB/CXCR7 通路促进巨噬细胞趋化。抑制 CXCR7 可显著逆转 R3cKO 小鼠中 FGFR3 缺失增强的巨噬细胞趋化和关节炎表型。
本研究确定了 FGFR3 在滑膜巨噬细胞募集和滑膜炎中的作用，为炎症相关关节炎的病理机制提供了新的见解。
