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482 INHIBITION OF MARROW STROMAL CELL OSTEOGENESIS BY POLYMETHYLMETHACRYLATE WEAR PARTICLES AND SOLUBLE FACTORS RELEASED FROM POLYMETHYLMETHACRYLATE PARTICLE-ACTIVATED MACROPHAGES.
  1. R. Chiu1,
  2. R. L. Smith1,
  3. S. B. Goodman1
  1. 1Stanford University School of Medicine, Stanford, CA

Abstract

Purpose Implant loosening of total joint arthroplasty may involve reduced bone formation resulting from the effects of prosthetic wear debris on osteoblast precursors. The inhibition of osteoblastic differentiation by wear debris may occur via a direct effect of wear particles on osteoblast progenitors or via an indirect effect of inhibitory cytokines released from particle-activated inflammatory cells. This study determined whether the direct exposure of marrow stromal cells to polymethylmethacrylate (PMMA) cement particles inhibits the ability of these cells to differentiate into osteoblasts and whether macrophages exposed to PMMA particles produce soluble factors that can indirectly inhibit osteogenesis.

Methods Osteogenesis was induced by growing murine marrow stromal cells (MSCs) in osteogenic medium containing 10−7 M dexamethasone, 50 μg/mL ascorbic acid, and 10 mM β-glycerophosphate for 15 days. Throughout their 15-day culture period in osteogenic medium, MSCs were either directly challenged with PMMA particles (0.30% v/v) or incubated in conditioned medium from Raw264.7 macrophage cultures that had been pretreated with PMMA particles (0.30% v/v) for 24 hours. To determine whether the effects of PMMA particles on MSC osteogenesis were reversible, particles were removed from MSC cultures after 1, 3, and 5 days of particle treatment, and cell growth in osteogenic medium was continued in the absence of particles for 15 more days. MSC cultures were assessed for the levels of cell proliferation, alkaline phosphatase expression, and bone mineralization at the end of the 15-day osteogenic period.

Results MSCs treated with PMMA particles throughout the 15-day culture period showed a 90 to 95% reduction in the levels of proliferation, alkaline phosphatase expression, and mineralization. MSCs treated with PMMA for only 5 days also showed a 90 to 95% reduction in these outcome parameters, whereas MSCs treated for ≤ 3 days showed a significantly diminished inhibitory response. MSCs incubated in conditioned medium from particle-treated macrophages showed a significant 53% reduction in mineralized nodules.

Conclusions This study has demonstrated that the direct exposure of MSCs to PMMA particles causes complete, irreversible suppression of osteogenesis. Macrophages exposed to PMMA particles also release soluble factors that can inhibit mineralization. The inhibition of bone growth during implant loosening is therefore due to the effects of wear particles and macrophage-released cytokines on osteoblast progenitors.

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