Recent studies suggest that osteoclasts may contribute to bone erosions in the joints of animal models of arthritis and human rheumatoid arthritis. We therefore adressed the question, can bone destruction occur in an osteoclast free model of arthritis? To answer this question, c-Fos knockout mice (c-fos-/-) were crossed with mice overexpressing human soluble TNF (huTNFtg). C-fos-/- mice lack osteoclasts and are therefore osteopetrotic since c-fos is essential for the signaling of osteoclast differentiation. HuTNFtg mice develop a severe and destructive arthritis through the signaling of huTNF via the p55 TNF receptor. The resulting four groups of mice (wildtype, huTNFtg, c-fos-/- and c-fos-/-/huTNFtg) were followed over 10 weeks and assessed for joint inflammation and joint destruction. Clinical features of arthritis, such as paw swelling and reduction in grip strength progressed equally in both huTNFtg and c-fos-/-/huTNFtg mice. Clinical features of arthritis were absent in c-fos-/- and wildtype mice. Quantitative histological evaluation of joint sections revealed no difference between huTNFtg and c-fos-/-/huTNFtg mice in the size of inflammatory synovial lesions. As previously described, huTNFtg mice showed severe bone erosions in all joint compartments. Bone resorption was characterized by the abundant presence of osteoclasts, as confirmed by cells positive staining for TRAP and the calcitonin receptor. Furthermore, the number of osteoclasts and the size of bone erosions were significant. In contrast, c-fos-/-/huTNFtg mice did not show any form of bone destruction despite the presence of severe inflammatory changes. C-fos-/-/huTNFtg mice were confirmed to lack osteoclasts by negative TRAP staining and the presence of osteopetrosis. Controls (c-fos-/- mice and wildtype mice) did not show histological signs of inflammation or bone erosion. In conclusion, these data clearly show that TNF-mediated bone erosion is triggered by osteoclasts, and the absence of osteoclasts turns TNF-mediated arthritis from destructive to non-destructive arthritis.