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.

Chemokine (C-C Motif) Receptor 1 Is Required for Efficient Recruitment of Neutrophils during Respiratory Infection with Modified Vaccinia Virus Ankara

“…infected with MVA and treated with the well-characterized CCR1 antagonist J-113863 (41,42) or an equivalent amount of vehicle. BAL was performed 16 h after infection, and cells in the BAL fluid were analyzed with flow cytometry.…”

NF-κB Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle

“…3 These chemokine gradients mediate migration of multiple cell types, including macrophages 4 and mesenchymal stem cells (MSCs). 5 Infiltrated MSCs have an immunomodulatory function and osteogenic ability. 6 A previous study showed that blocking MIP1a using a receptor antagonist mitigated osteolysis induced by ultrahigh-molecular-weight polyethylene (UHMWPE) particles in a murine model, suggesting that MSCs can protect particle-induced osteolysis in a confined region.…”

“…6 A previous study showed that blocking MIP1a using a receptor antagonist mitigated osteolysis induced by ultrahigh-molecular-weight polyethylene (UHMWPE) particles in a murine model, suggesting that MSCs can protect particle-induced osteolysis in a confined region. 5 NF-kB is a key transcriptional factor in inflammatory reactions. Recently, we demonstrated that suppression of NF-kB activity using decoy oligodeoxynucleotide (ODN) in primary mouse macrophages or the human THP1 macrophage cell line decreased the expression of multiple cytokines and chemokines in the presence of wear particles and endotoxin.…”

“…Thus, when evaluating possible treatments for periprosthetic osteolysis, the potential adverse effects of these interventions on other neighboring cells must be considered. Given the fundamental role of MSCs in protecting wear particle-induced osteolysis, 5 the biological effects of NF-kB on MSCs are highly relevant.…”

The Biologic Response to Bearing Materials

“…Release of MCP-1 and macrophage inflammatory protein 1α induce the systemic recruitment of macrophages and mesenchymal stem cells. 4,5 Locally activated macrophages undergo polarization toward the M1 (proinflammatory) phenotype. 6 M1 macrophages produce primarily proinflammatory mediators, including TNF-α, IL-1, and IL-6, and express inducible nitric oxide synthase.…”