CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.
CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.
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DOI：
10.1136/annrheumdis-2016-210426
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发表时间：
2017-05
影响因子：
27.4
通讯作者：
Robinson WH
中科院分区：
文献类型：
--
作者：
Raghu H;Lepus CM;Wang Q;Wong HH;Lingampalli N;Oliviero F;Punzi L;Giori NJ;Goodman SB;Chu CR;Sokolove JB;Robinson WH
虽然各种单核细胞趋化因子系统在骨关节炎（OA）中表达增加，但在介导单核细胞/巨噬细胞募集到OA关节中的趋化因子和趋化因子受体的等级仍然不清楚。在这里，我们研究了CCL2/CCR2和CCL5/ CCR5趋化因子轴在OA发病中的相对贡献。Ccl2-, Ccr2-， Ccl5-和ccr5缺陷小鼠和对照小鼠接受内侧半月板手术不稳定以诱导OA。使用CCL2合成抑制剂bindarit和CCR2拮抗剂RS-504393，研究了阻断小鼠OA CCL2/CCR2信号传导的药理效用。采用微阵列分析、多重细胞因子测定和免疫染色相结合的方法，研究了无骨性关节炎患者和已确诊骨性关节炎患者滑膜组织和液体中单核细胞化学引诱剂的水平。缺乏CCL2或CCR2的小鼠，而不缺乏CCL5或CCR5的小鼠，可以通过关节中局部单核细胞/巨噬细胞数量的减少来预防OA。在OA患者的滑液中，CCR2配体（CCL2、CCL7和CCL8）水平升高，但CCR5配体（CCL3、CCL4和CCL5）水平未升高。我们发现CCR2+细胞在人OA滑膜中丰富，并且CCR2+巨噬细胞系侵入OA软骨并与OA软骨侵蚀有关。此外，阻断CCL2/CCR2信号可显著减轻小鼠OA中的巨噬细胞积聚、滑膜炎和软骨损伤。我们的研究结果表明，通过CCL2/CCR2募集的单核细胞，而不是通过CCL5/CCR5募集的单核细胞，在OA中传播炎症和组织损伤。选择性靶向CCL2/CCR2系统是一种很有前途的OA治疗方法。
While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/ CCR5 chemokine axes in OA pathogenesis. Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains. Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA. Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.
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DOI：
10.1084/jem.20141539
发表时间：
2015-04-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dal-Secco D;Wang J;Zeng Z;Kolaczkowska E;Wong CH;Petri B;Ransohoff RM;Charo IF;Jenne CN;Kubes P
通讯作者：
Kubes P
影响因子：
--
作者：
Haringman, Jasper J.;Gerlag, Danielle M.;Tak, Paul P.
通讯作者：
Tak, Paul P.
影响因子：
13.6
作者：
de Lema, GP;Maier, H;Luckow, B
通讯作者：
Luckow, B
影响因子：
13.3
作者：
Appleton, C. Thomas G.;Usmani, Shirine E.;Beier, Frank
通讯作者：
Beier, Frank
骨关节炎的炎症。
影响因子：
5.1
作者：
Goldring MB;Otero M
通讯作者：
Otero M