Skeletal and extraskeletal implications of mutations in P62/SQSTM1 gene: from animal studies to humans
Paget’s disease of bone (PDB) is a focal disorder of bone metabolism characterized by enlarged and deformed bones. Although patients can be asymptomatic in the early phases, most of them develop complications such as deafness, fracture, osteoarthritis and nerve compression syndromes. An increased prevalence of cardiovascular calcifications has been also described in a subset of PDB cases. All these complications significantly affect the morbidity and the quality of life. Moreover, some pagetic bones may undergo neoplastic degeneration in osteosarcoma or less frequently giant cell tumors.The etiology of PDB has remained largely unknown for several decades. Since 2002, mutations in p62/SQSTM1 gene encoding p62, an ubiquitary protein involved in selective autophagy, protection from oxidative stress and as a scaffold in a number of signalling pathways, have been associated with the disorder in up to 50% and 10% of familial and sporadic cases, respectively. Even though a consistent number of mutations affect the N-terminal UBA domain of p62, mutations at other functional domains have been also described, suggesting a more complex functional mechanism affecting different cell functions. More recently p62/SQSTM1 mutations have been described in some patients with neurodegenerative disorders. Moreover, p62/SQSTM1 knockout mice exhibit extra-skeletal manifestations such as enhanced adipogenesis, insulin resistance, enhanced tumorigenesis and vascular calcifications.
Thus, further studies are expected to better characterize the role of p62/SQSTM1 protein and of its mutations in different tissues with potential impact not only for the management of PDB but also for revealing new molecular targets involved in common age related conditions such as insulin resistance, neuro degeneration, tumorigenesis and cardiovascular pathology.