title: CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.
abstract: OBJECTIVE
  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- andCcr5-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.
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.|VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Raghu
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.|VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Christin M
authors.initials: CM
authors.lastname: Lepus
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.|VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.|VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Wong
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.|VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Nithya
authors.initials: N
authors.lastname: Lingampalli
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Oliviero
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Punzi
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, California, USA.|Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Giori
authors.affiliation: Department of Orthopedic Surgery and Department of Bioengineering, Stanford University, Stanford, California, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, California, USA.|Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Constance R
authors.initials: CR
authors.lastname: Chu
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.|VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Sokolove
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.|VA Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism*; D002633:Chemotaxis; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007958:Leukocyte Count; D008264:Macrophages; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013582:Synovial Fluid / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C483024:CCL5 protein, human; C515334:CCR2 protein, human; C584933:CCR5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D007191:Indazoles; D011422:Propionates; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019713:Receptors, CCR5; C079489:bindarit
keywords: Chemokines; Cytokines; Inflammation; Osteoarthritis