Even though administration of high doses of exogenous TNF leads to the formation of osteoclast-like cells in RANK knockout mice at the site of calvarial injection (41), introduction of the Tg3647 TNF-expressing transgenic model displaying late onset arthritis in a RANK knockout background, showed that upon TNF overexpression osteoclastogenesis does not occur in the absence of RANKL/RANK signaling (42). This evidence concerns the gene TNFSF11 and arthritic joint disease.