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STATINS ATTENUATE POLYMETHYLMETHACRYLATE - MEDIATED MONOCYTE ACTIVATION: A PROPHYLAXIS FOR ASEPTIC LOOSENING

7th Congress of the European Federation of National Associations of Orthopaedics and Traumatology, Lisbon - 4-7 June, 2005



Abstract

Background: Periprosthetic osteolysis precipitates aseptic component loosening, increases periprosthetic fracture risk and through massive bone loss, complicates revision surgery.

Its pathogenesis is based upon the generation of wear debris particles which trigger synovial macrophage activation. Statins, inhibitors of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-Co-A) reductase, have revolutionised the treatment of hypercholesterolaemia and cardiovascular disease. The antiinflammatory properties of HMG-CoA reductase inhihitors or the statin family are well recognised. We investigated the effects of ceriv-astatin in attenuating the activation of human macrophages by polymethylmethacrylate (PMMA) particles.

Methods: Polymethylmethacrylate-particle-stimulated human macrophages were cultured in vitro with cerivastatin at 75 and 150micromols/litre. TNF- alpha (tumour necrosis factor alpha) and MCP-1 (monocyte chemotactic protein) expression were determined using ELISA. UO126, a Raf/MEK/ERK intracellular transduction pathway inhibitor, was utilised to identify the mitogen activated protein kinase (MAP- Kinase) pathway involved and western blotting was used to demonstrate the effect of cerivastatin on this pathway.

Results Human monocyte/macrophage cultures were activated by PMMA particles evidenced by TNF- alpha and MCP-1 expression(p< 0.05). This activation was consistently attenuated by cerivastatin therapy. Similarily, PMMA activation was attenuated by the Raf/MEK/ERK inhibitor, UO126.

Western blotting confirmed Raf/MEK/ERK down-regulation by cerivastatin, establishing a mechanism for its anti-inflammatory effects.

Conclusion We have demonstrated in vitro, that statins can abrogate particle induced inflammatory responses in a dose dependent manner and this is mediated intra-cellularily through its effect on the Raf/MEK/ERK transduction pathway. We propose that by attenuating this inflammatory response, the associated subsequent osteoclast activation and osteolysis is attenuated. Statins therefore may have role in promoting implant longevity

Theses abstracts were prepared by Professor Roger Lemaire. Correspondence should be addressed to EFORT Central Office, Freihofstrasse 22, CH-8700 Küsnacht, Switzerland.