Macrophage colony-stimulating factor and interleukin-6 release by periprosthetic cells stimulates osteoclast formation and bone resorption

Periprosthetic bone loss is an important contributory factor for aseptic lo osening of total joint replacements. It has recently been shown that osteoc last precursor cells are present in the wear particle-associated macrophage infiltrate found in the membrane surrounding loose implants and that these cells are capable of differentiating into osteoclastic bone-resorbing cell s. Long-term co-culture of arthroplasty-derived macrophages and the rat ost eoblast-like cell line, UMR-106, in the presence of 1.25(OH)(2)D-3 results in the formation of numerous multinucleated cells that are positive for tar trate-resistant acid phosphatase and vitronectin receptor and capable of ex tensive lacunar bone resorption. The aim of this study was to determine the effect of cytokines/growth factors, known to be present in the arthroplast y membrane, on this process of osteoclast differentiation. During osteoclas t formation, increased levels of macrophage colony-stimulating factor, inte rleukin-6, and to a lesser extent, interleukin-1 beta, but not tumour necro sis factor alpha, were detected in the co-culture supernatants. Addition of neutralising antibodies to human interleukin-1 beta or tumour necrosis fac tor alpha to the co-culture system did not inhibit osteoclast formation. In contrast, co-cultures to which neutralising antibodies to human macrophage colony-stimulating factor or interleukin-6 were added contained fewer cell s positive for tartrate resistant acid phosphatase and vitronectin receptor and formed significantly fewer resorption pits. Time-course studies showed that macrophage colony-stimulating factor and interleukin-6 increase osteo clast formation mainly in the early stages of osteoclast differentiation. T hese results indicate that the release of macrophage colony stimulating fac tor and interleukin-6 by activated cells in the arthroplasty membrane is li kely to contribute to pathological bone resorption associated with aseptic loosening by stimulating differentiation of mononuclear phagocyte osteoclas t precursors into mature bone-resorbing cells.