我校陈林教授团队在Annals of the Rheumatic Diseases发表研究成果 —— FGFR3缺失通过上调CXCR7增强CXCL12依赖的巨噬
发布人:zhangyilin 发布时间:6/18/2020 11:16:29 AM  浏览次数:261次
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FGFR3缺失通过上调CXCR7增强CXCL12依赖的巨噬细胞趋化运动并加重小鼠的关节破坏

 

旷梁    陈林

 

骨关节炎是运动系统常见疾病,也是导致病患丧失行动能力的重要原因之一。由于骨关节炎发病机制复杂,至今仍缺乏有效的治疗手段。近年来,骨关节炎被认为是一种全关节疾病,其病理改变包括关节软骨磨损、软骨下骨重构、滑膜肿胀,炎性细胞浸润以及骨赘形成等,尤其是巨噬细胞介导的滑膜炎症在骨关节炎的发生发展中备受关注。

既往研究显示,FGFR3全敲小鼠及软骨内特异性敲除小鼠都会出现关节软骨退变加剧,并促进关节炎的发生发展。但FGFR3是否可以通过调节巨噬细胞炎症反应进而影响关节炎进程尚不明确。

本研究建立了FGFR3巨噬细胞条件性敲除小鼠,通过体内及体外实验发现FGFR3是调节滑膜巨噬细胞募集的关键因子;巨噬细胞FGFR3缺失可以促进滑膜炎症,并导致小鼠自发性多关节破坏。通过巨噬细胞RNA测序分析进一步发现FGFR3缺失可激活NF-κB通路促进巨噬细胞表达趋化因子受体CXCR7并增强CXCL12依赖的巨噬细胞趋化运动。巨噬细胞募集是滑膜炎症反应的重要环节,本研究结果为临床上抑制滑膜巨噬细胞募集进而抑制滑膜炎症提供了潜在治疗策略。靶向单核/巨噬细胞中FGFR3/CXCR7通路可能是预防和早期治疗关节炎的可行方案。

此外,本研究还发现在骨关节炎患者的外周血单核细胞中FGFR3的表达水平较低,而相应的CXCR7表达水平较高。该结果提示外周血单核细胞的FGFR3或CXCR7蛋白水平可能作为临床上预测骨关节炎发生的潜在标志物,为关节炎的早期诊断提供新策略。以上研究结果于2020 年1月发表于《Annals of the Rheumatic Diseases》(IF=14.299).

 

附:文章摘要

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

 

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.

 

Keywords: Fibroblast Growth Factor Receptor 3, Macrophage, Chemotaxis, Synovitis, Arthritis.

 

全文链接:https://ard.bmj.com/content/79/1/112.long

 


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