Effect of a CCR1 receptor antagonist on systemic trafficking of MSCs and polyethylene particle-associated bone loss

Biomaterials. 2012 May;33(14):3632-8. doi: 10.1016/j.biomaterials.2012.02.003. Epub 2012 Feb 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocompatible Materials / adverse effects*
  • Cell Differentiation
  • Cell Movement / drug effects
  • Chemotaxis / drug effects
  • Humans
  • Joint Prosthesis / adverse effects
  • Male
  • Materials Testing
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Osteolysis / etiology
  • Osteolysis / pathology
  • Polyethylenes / adverse effects*
  • Prosthesis Failure / etiology
  • Receptors, CCR1 / antagonists & inhibitors*
  • Receptors, CCR1 / deficiency
  • Receptors, CCR1 / genetics
  • Xanthenes / pharmacology

Substances

  • Biocompatible Materials
  • Ccr1 protein, mouse
  • Polyethylenes
  • Receptors, CCR1
  • Xanthenes
  • ultra-high molecular weight polyethylene
  • UCB 35625