Recent advances in understanding the molecular basis of Paget disease of bone

Paget disease of bone (PDB) is a relatively common disorder characterised by increased bone turnover within discrete lesions throughout the skeleton. The condition has a strong genetic component, with mutations affecting the SQSTM1 gene that encodes the p62 protein often found in PDB patients, although environmental factors also play an important role in disease aetiology. The precise disease mechanism(s) in familial forms and sporadic forms of PDB is unclear, although defective RANK-NF-kappaB signalling has been suggested to contribute to the increased activity of pagetic osteoclasts in the former. Here, there is a review of recent advances in the understanding of the molecular basis of PDB with particular emphasis on findings since 2008, and focus on newly defined functions of the p62 protein upon which SQSTM1 mutations may impact in the development of the pagetic phenotype.