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Translational science
FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice
  1. Liang Kuang1,
  2. Jiangyi Wu2,
  3. Nan Su1,
  4. Huabing Qi1,
  5. Hangang Chen1,
  6. Siru Zhou1,
  7. Yan Xiong3,
  8. Xiaolan Du1,
  9. Qiaoyan Tan1,
  10. Jing Yang1,
  11. Min Jin1,
  12. Fengtao Luo1,
  13. Junjie Ouyang1,
  14. Bin Zhang1,
  15. Zuqiang Wang1,
  16. Wanling Jiang1,
  17. Liang Chen1,
  18. Shuai Chen1,
  19. Ziming Wang3,
  20. Peng Liu3,
  21. Liangjun Yin4,
  22. Fengjin Guo5,
  23. Chuxia Deng6,
  24. Di Chen7,
  25. Chuanju Liu8,
  26. Yangli Xie1,
  27. Zhenhong Ni1,
  28. Lin Chen1
  1. 1 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
  2. 2 Center for Joint Surgery, Southwest Hospital, Army Medical University, Chongqing, China
  3. 3 Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing, China
  4. 4 Department of Orthopaedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
  5. 5 Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing, China
  6. 6 Faculty of Health Sciences, University of Macau, Taipa, Macau
  7. 7 Biochemistry, Rush University Medical Center, Chicago, Illinois, USA
  8. 8 Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York City, New York, USA
  1. Correspondence to Professor Lin Chen, 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, Chongqing, China; linchen70{at}163.com; Dr Zhenhong Ni; nizhenhong1986{at}163.com; Dr Yangli Xie; xieyangli841015{at}163.com

Abstract

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.

  • synovitis
  • chemokines
  • inflammation
  • arthritis
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Footnotes

  • 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.

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