Raghu Harini, Lepus Christin M, Wang Qian, Wong Heidi H, Lingampalli Nithya, Oliviero Francesca, Punzi Leonardo, Giori Nicholas J, Goodman Stuart B, Chu Constance R, Sokolove Jeremy B, Robinson William H
Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.
VA Palo Alto Health Care System, Palo Alto, California, USA.
Ann Rheum Dis. 2017 May;76(5):914-922. doi: 10.1136/annrheumdis-2016-210426. Epub 2016 Dec 13.
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.
-, -, - and -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.
虽然多种单核细胞趋化因子系统在骨关节炎（OA）中的表达增加，但趋化因子和趋化因子受体在介导单核细胞/巨噬细胞募集到OA关节中的层级关系仍不清楚。在此，我们研究了CCL2/CCR2与CCL5/CCR5趋化因子轴在OA发病机制中的相对作用。
将CCL2基因敲除、CCR2基因敲除、CCL5基因敲除、CCR5基因敲除小鼠及对照小鼠进行内侧半月板失稳手术以诱导OA。使用CCL2合成抑制剂bindarit和CCR2拮抗剂RS-504393研究阻断小鼠OA中CCL2/CCR2信号传导的药理作用。使用微阵列分析、多重细胞因子检测和免疫染色相结合的方法，研究无OA的关节损伤患者和已患OA患者的滑膜组织和滑液中单核细胞趋化因子的水平。
缺乏CCL2或CCR2但不缺乏CCL5或CCR5的小鼠对OA具有抵抗力，同时其关节内局部单核细胞/巨噬细胞数量减少。在OA患者的滑液中，CCR2配体（CCL2、CCL7和CCL8）水平升高，而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⁺巨噬细胞排列、侵入并与OA软骨侵蚀相关。此外，阻断CCL2/CCR2信号传导可显著减轻小鼠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而非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系统代表了一种有前景的OA治疗方法。
