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PURPOSE: TNFalpha and IL-1alpha are proinflammatory cytokines that are abundant in periprosthetic tissues. These cytokines stimulate bone resorption and have recently been shown to directly induce osteoclast formation in mouse marrow cultures. We examined whether TNFalpha and IL-1alpha can directly induce osteoclast formation from human arthroplasty-derived (CD14(+)) macrophages by a mechanism independent of RANKL-induced osteoclastogenesis. METHODS: TNFalpha and M-CSF (+/-IL-1alpha) were added to cultures of magnetically sorted (CD14(+)) and unsorted (CD14(+)/CD14(-)) cells isolated from the pseudomembrane of loosened hip arthroplasties. Osteoprotegerin (OPG), RANK:Fc and antibodies to TNF receptors (p55 and p75) were added to these cultures to distinguish the pathway of osteoclastogenesis. Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR) and lacunar resorption. RESULTS: The addition of TNFalpha (+/-IL-1alpha) resulted in differentiation of CD14(+) macrophages into TRAP(+) and VNR(+) multinucleated cells capable of extensive lacunar resorption. Both OPG and RANK:Fc (which inhibit RANKL-induced osteoclastogenesis) did not block osteoclastogenesis. The addition of antibodies directed against the p55 receptor subunit of TNF resulted in significant inhibition of osteoclast formation and lacunar resorption. CONCLUSIONS: Our results indicate that, in the presence of M-CSF, TNFalpha is sufficient for inducing human osteoclast differentiation from arthroplasty macrophages and that TNFalpha acts synergistically with IL-1alpha to stimulate lacunar resorption. This process is distinct from the RANK/RANKL signalling pathway and is likely to operate in periprosthetic tissues when there is heavy wear particle deposition and cytokine production.

Original publication




Journal article


Journal of orthopaedic research : official publication of the orthopaedic research society

Publication Date





73 - 80


Nuffield Department of Orthopaedic Surgery, University of Oxford, Oxford OX3 7LD, UK.


Acetabulum, T-Lymphocytes, Cells, Cultured, Fibroblasts, Macrophages, Osteoclasts, Humans, Bone Resorption, Osteolysis, Prosthesis Failure, Glycoproteins, Tumor Necrosis Factor-alpha, Antigens, CD14, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Receptors, Cytoplasmic and Nuclear, Antineoplastic Agents, Antigens, CD, Antibodies, Signal Transduction, Aged, Aged, 80 and over, Middle Aged, Female, Male, Osteoprotegerin