FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice

被引：65

作者：

Kuang, Liang ^{[1
]}

Wu, Jiangyi ^{[2
]}

Su, Nan ^{[1
]}

Qi, Huabing ^{[1
]}

Chen, Hangang ^{[1
]}

Zhou, Siru ^{[1
]}

Xiong, Yan ^{[3
]}

Du, Xiaolan ^{[1
]}

Tan, Qiaoyan ^{[1
]}

Yang, Jing ^{[1
]}

Jin, Min ^{[1
]}

Luo, Fengtao ^{[1
]}

Ouyang, Junjie ^{[1
]}

Zhang, Bin ^{[1
]}

Wang, Zuqiang ^{[1
]}

Jiang, Wanling ^{[1
]}

Chen, Liang ^{[1
]}

Chen, Shuai ^{[1
]}

Wang, Ziming ^{[3
]}

Liu, Peng ^{[3
]}

Yin, Liangjun ^{[4
]}

Guo, Fengjin ^{[5
]}

Deng, Chuxia ^{[6
]}

Chen, Di ^{[7
]}

Liu, Chuanju ^{[8
]}

Xie, Yangli ^{[1
]}

Ni, Zhenhong ^{[1
]}

Chen, Lin ^{[1
]}

机构：

[1] Army Med Univ, State Key Lab Trauma Burns & Combined Injury, Lab Prevent & Rehabil Training Injuries,Daping Ho, Ctr Bone Metab & Repair,Trauma Ctr,Res Inst Surg, Chongqing, Peoples R China

[2] Army Med Univ, Southwest Hosp, Ctr Joint Surg, Chongqing, Peoples R China

[3] Army Med Univ, Daping Hosp, Dept Orthoped, Chongqing, Peoples R China

[4] Chongqing Med Univ, Affiliated Hosp 2, Dept Orthoped, Chongqing, Peoples R China

[5] Chongqing Med Univ, Dept Cell Biol & Genet, Core Facil Dev Biol, Chongqing, Peoples R China

[6] Univ Macau, Fac Hlth Sci, Taipa, Macau, Peoples R China

[7] Rush Univ, Med Ctr, Biochem, Chicago, IL 60612 USA

[8] NYU, Med Ctr, Sch Med, Dept Orthopaed Surg, New York, NY 10016 USA

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2020年 / 79卷 / 01期

基金：

中国国家自然科学基金;

关键词：

FACTOR-KAPPA-B; RHEUMATOID-ARTHRITIS; FACTOR-I; OSTEOARTHRITIS; CHONDROCYTES; INFLAMMATION; ACTIVATION; EXPRESSION; SYNOVIUM; GROWTH;

D O I：

10.1136/annrheumdis-2019-215696

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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 mu CT 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-.B/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.

引用

页码：112 / 122

页数：11

共 47 条

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Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID mice [J].