Ubiquitin-mediated signalling and Paget's disease of bone

Multiple steps in the RANK-NF-kappa B signalling pathway are regulated by ubiquitylation. Mutations affecting different components of this pathway, including the ubiquitin binding p62 signalling adapter protein, are found in patients with Paget's disease of bone or related syndromes. Here, we review the molecular defects and potential disease mechanisms in these conditions and conclude that the mutations may confer a common increased sensitivity of osteoclasts to cytokines, resulting in disordered NF-kappa B-dependent osteoclast function. Modulation of the osteoclast RANK-NF-kappa B signalling axis may represent a viable therapeutic strategy for Paget's disease and other conditions where excessive bone resorption or remodelling is a feature.