title: Effect of a CCR1 receptor antagonist on systemic trafficking of MSCs and polyethylene particle-associated bone loss.
abstract: Particle-associated periprosthetic osteolysis remains a major issue in joint replacement. Ongoing bone loss resulting from wear particle-induced inflammation is accompanied by continued attempts at bone repair. Previously we showed that mesenchymal stem cells (MSCs) are recruited systemically to bone exposed to continuous infusion of ultra high molecular weight polyethylene (UHMWPE) particles. The chemokine-receptor axis that mediates this process is unknown. We tested two hypotheses: (1) the CCR1 receptor mediates the systemic recruitment of MSCs to UHMWPE particles and (2) recruited MSCs are able to differentiate into functional mature osteoblasts and decrease particle-associated bone loss. Nude mice were allocated randomly to four groups. UHMWPE particles were continuously infused into the femoral shaft using a micro-pump. Genetically modified murine wild type reporter MSCs were injected systemically via the left ventricle. Non-invasive imaging was used to assay MSC migration and bone mineral density. Bioluminescence and immunohistochemistry confirmed the chemotaxis of reporter cells and their differentiation into mature osteoblasts in the presence of infused particles. Injection of a CCR1 antagonist decreased reporter cell recruitment to the UHMWPE particle infusion site and increased osteolysis. CCR1 appears to be a critical receptor for chemotaxis of MSCs in the presence of UHMWPE particles. Interference with CCR1 exacerbates particle-induced bone loss.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, Redwood City, CA 94063, USA. egibon@stanford.edu
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gibon
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Rao
authors.forename: Stefan
authors.initials: S
authors.lastname: Zwingenberger
authors.forename: Barbara
authors.initials: B
authors.lastname: Batke
authors.forename: Roberto
authors.initials: R
authors.lastname: Valladares
authors.forename: Robert L
authors.initials: RL
authors.lastname: Smith
authors.forename: Sandip
authors.initials: S
authors.lastname: Biswal
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects*; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D007595:Joint Prosthesis / Q000009:adverse effects; D008297:Male; D008422:Materials Testing; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010014:Osteolysis / Q000209:etiology / Q000473:pathology; D011095:Polyethylenes / Q000009:adverse effects*; D011475:Prosthesis Failure / Q000209:etiology; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D001672:Biocompatible Materials; C515301:Ccr1 protein, mouse; D011095:Polyethylenes; D054389:Receptors, CCR1; D014966:Xanthenes; C111601:ultra-high molecular weight polyethylene; C413447:UCB 35625