Objectives 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.
Methods 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.
Results 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.
Conclusions 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.
Statistics from Altmetric.com
Handling editor Tore K Kvien
HR and CML are co-first authors and contributed equally to this work.
Contributors HR and CML performed key studies. HR, QW and HHW conducted the studies of osteoarthritis in mouse models. CML and HR performed immunofluorescent and H&E staining of synovium provided by NJG, SBG and CRC. HR analysed these images. HR and NL conducted ELISA analyses, and NL performed Luminex cytokine profiling using synovial fluids provided by JBS, CRC, LP and FO. HR cultured and performed the in vitro stimulation assays on OA synovial fibroblasts. HR and NL analysed gene expression datasets downloaded from NCBI. CRC and JBS provided key scientific input. HR and WHR wrote and edited the manuscript. All authors reviewed the data and approved the manuscript.
Funding These studies were supported by VA RR&D Merit Review Awards I01BX002345, I01RX000934 and I01RX000588 to WHR.
Competing interests None.
Ethics approval Stanford Institutional Review Board, University of Padova IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.