Mutant SQSTM1/p62 Signaling in Paget's Disease of Bone

Paget's disease of bone (PDB) is characterized by focal lesions of excessive bone turnover initiated by hyperactive osteoclasts and compensated for by changes in osteoblast activity. The primary defect in PDB appears to reside in the bone-resorbing osteoclasts, although inherent abnormalities have also been reported in bone-forming osteoblasts. Mutations affecting the SQSTM1/p62 gene are common in patients with hereditary and sporadic PDB and can also occur de novo within lesions. The SQSTM1/p62 protein has important regulatory roles in several cellular signaling pathways that have relevance to osteoclast differentiation, activity or survival, including nuclear factor kappa B signaling, the oxidative-stress induced Keap1/Nrf2 pathway, apoptosis, and protein turnover. We outline the current understanding of the impact of mutant SQSTM1/p62 on these inter-regulated pathways with respect to the pathophysiology of PDB.