FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice
| Autor: | Liang Chen, Zuqiang Wang, Hangang Chen, Junjie Ouyang, Nan Su, Chuan-ju Liu, Zhenhong Ni, Siru Zhou, Yan Xiong, Peng Liu, Lin Chen, Fengtao Luo, Liangjun Yin, Jiangyi Wu, Huabing Qi, Jing Yang, Qiaoyan Tan, Bin Zhang, Shuai Chen, Wanling Jiang, Ziming Wang, Xiaolan Du, Min Jin, Chu-Xia Deng, Yangli Xie, Feng-Jin Guo, Liang Kuang, Di Chen |
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| Rok vydání: | 2019 |
| Předmět: |
Cartilage
Articular musculoskeletal diseases 0301 basic medicine Pathology medicine.medical_specialty Immunology Arthritis Monocytes General Biochemistry Genetics and Molecular Biology Macrophage chemotaxis Mice 03 medical and health sciences 0302 clinical medicine Rheumatology Synovitis Osteoarthritis Conditional gene knockout Synovial joint Animals Humans Receptor Fibroblast Growth Factor Type 3 Immunology and Allergy Medicine Macrophage Myeloid Cells Gait Mice Knockout Receptors CXCR 030203 arthritis & rheumatology business.industry Chemotaxis Macrophages Monocyte Synovial Membrane NF-kappa B medicine.disease Chemokine CXCL12 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Joints business |
| Zdroj: | Annals of the Rheumatic Diseases. 79:112-122 |
| ISSN: | 1468-2060 0003-4967 |
| Popis: | ObjectivesThis study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis.MethodsMice 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.ResultsR3cKO 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.ConclusionsOur 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. |
| Databáze: | OpenAIRE |
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