Objective-In aseptic loosening, a heavy macrophage response to biomaterial wear particles is commonly found in arthroplasty tissues. The aim of this study was to discover if these cells contribute to the bone resorption of aseptic loosening by diVerentiating into osteoclasts. macrophage-osteoclast diVerentiation may represent an important cellular mechanism whereby osteolysis is eVected in aseptic loosening. (Ann Rheum Dis 1997;56:414-420) Aseptic loosening is the commonest cause of late failure of cemented and uncemented joint replacements. It is associated with the presence of a prominent foreign body macrophage response to polymeric and metallic wear particles in the pseudocapsule and pseudomembrane surrounding the implant. Methods-Macrophages

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Mononuclear precursors of the human osteoclast have been identified in both bone marrow and the circulation in man, but osteoclast membership of the mononuclear phagocyte system (MPS) and its precise cellular ontogeny remain controversial. We isolated human hematopoietic marrow cells, blood monocytes, and peritoneal macrophages and incubated each of these cell populations with UMR106 osteoblast-like cells on glass coverslips and dentine slices in both the presence and absence of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), macrophage-colony stimulating factor (M-CSF), and dexamethasone. Cells isolated from peripheral blood and peritoneal dialysis fluid were positive only for monocyte/macrophage markers (CD11a, CD11b, CD14, and HLA-DR) and negative for osteoclast markers [tartrate-resistant acid phosphatase (TRAP), vitronectin reception (VNR), and calcitonin (CT) receptors and did not form resorption pits on dentine slices after 24 hours in culture. Similarly marrow cells did not form resorption pits on dentine slices after 24 hours in culture. However, after 14 days in co-culture with UMR106 cells, in the presence of 1,25(OH)2D3 and M-CSF, numerous TRAP, CT receptor, and VNR-positive multinucleated cells capable of extensive lacunar resorption were formed in co-cultures of all these preparations. The presence of 1,25 (OH)2D3, M-CSF, and UMR106 were absolute requirements for osteoclast differentiation. It is concluded that precursor cells capable of osteoclast differentiation are present in the marrow compartment, the monocyte fraction of peripheral blood, and in the macrophage compartment of extraskeletal tissues and that these cells are capable of differentiating into mature functional osteoclasts. These findings argue in favor of osteoclast membership of the human MPS.

(1,25(OH)2D3)'9-22; the mononuclear and multinucleated cells formed in these cocultures show all the phenotypic characteristics of osteoclasts, including expression of tartrate resistant acid phosphatase (TRAP), calcitonin receptors (CTR), and most importantly, the functional ability to produce resorption lacunae in bone. In the context of an inflammatory disease such as rheumatoid arthritis, where there is a heavy macrophage infiltrate in synovial tissues, osteoclast differentiation by monocytes and macrophages could represent an important mechanism for the pathogenesis of bone destruction. In this study we have sought to determine whether this cellular mechanism of osteoclast formation and pathological bone resorption operates in rheumatoid arthritis. Peripheral blood monocytes and synovial macrophages from rheumatoid arthritis patients were co-cultured with osteoblastic cells in the presence and absence of humoral factors which are known to be important in mouse osteoclast formation, in order to determine the cellular and humoral conditions for mononuclear phagocyte-osteoclast differentiation in rheumatoid arthritis.2'25