title: Selective inhibition of the MCP-1-CCR2 ligand-receptor axis decreases systemic trafficking of macrophages in the presence of UHMWPE particles.
abstract: The biological mechanisms leading to periprosthetic osteolysis involve both chemokines and the monocyte/macrophage cell lineage. Whether MCP-1 plays a major role in macrophage recruitment in the presence of wear particles is unknown. We tested two hypotheses: (1) that exogenous local delivery of MCP-1 induces systematic macrophage recruitment and (2) that blockade of the MCP-1 ligand-receptor axis decreases macrophage recruitment and osteolysis in the presence of ultra high molecular weight polyethylene (UHMWPE) particles. Six groups of nude mice were used. We used non-invasive imaging to assay macrophage recruitment and osteolysis. A murine macrophage cell line and primary wild type and CCR2 knockout murine macrophages were used as the reporter cells. Particles were infused into the femoral canal. Bioluminescence and immunohistochemical staining were used to confirm the migration of reporter cells. Locally infused MCP-1 induced systemic macrophage trafficking to bone. Injection of MCP-1 receptor antagonist significantly decreased reporter cell recruitment to bone infused with UHMWPE particles and decreased osteolysis. Systemic migration of reporter cells to infused particles was decreased when the reporter cells were deficient in the CCR2 receptor. Interruption of the MCP-1 ligand-receptor axis appears to be a viable strategy to mitigate trafficking of macrophages and osteolysis due to UHMWPE particles.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gibon
authors.forename: Ting
authors.initials: T
authors.lastname: Ma
authors.forename: Pei-Gen
authors.initials: PG
authors.lastname: Ren
authors.forename: Kate
authors.initials: K
authors.lastname: Fritton
authors.forename: Sandip
authors.initials: S
authors.lastname: Biswal
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Lane
authors.initials: L
authors.lastname: Smith
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
mesh_terms: D000818:Animals; D019643:Arthroplasty, Replacement / Q000009:adverse effects; D015519:Bone Density / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D005269:Femur / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008970:Molecular Weight; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D010316:Particle Size; D020959:Polyethylene / Q000737:chemistry / Q000494:pharmacology*; D011475:Prosthesis Failure / Q000209:etiology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D020959:Polyethylene