Interestingly, CYLD has been shown to negatively regulate RANK signalling and osteoclastogenesis in mice [65]. Mice with a genetic deficiency of CYLD have aberrant osteoclast differentiation and develop severe osteoporosis. Osteoclast precursors of these mice are hyper-responsive to RANKL-induced differentiation and produce more and larger osteoclasts. CYLD expression is markedly upregulated under conditions of RANKL-induced osteoclastogenesis and is recruited to ubiquitinated TRAF6 via the ubiquitin-binding adaptor protein p62 (also known as sequestosome 1) [65], followed by the CYLD-mediated deubiquitination of TRAF6. In this context, it is worth mentioning that transgenic mice expressing a mutated form of p62 also display abnormal osteoclastogenesis and develop progressive bone loss [66]. These findings suggest that CYLD-mediated inhibi-tion of RANK-induced NF-κB signalling plays a key role in the negative regulation of osteoclastogenesis and indicate CYLD as a potential genetic factor involved in the pathology of bone disorders such as RA.