Genetic aspects of Paget’s disease of bone

Paget’s disease of bone (PDB) is a metabolic bone disease characterized by excessive bone resorption and formation due to increased osteoclasts activity. PDB mostly runs asymptomatically, although increased bone turnover can be present and in approximately 30% of patients bone abnormalities, such as bone pain and deformities, pathological fractures and deafness may occur. The existence of familial aggregation of PDB has been reported in numerous papers, describing the occurrence of disease in successive generations. It has been clearly established that PDB is genetically heterogeneous with several loci able to confer an increased susceptibility to develop this bone metabolic disorder. In particular, the PDB3 locus in chromosome 5q35-qter hosts the sequestosome1/ p62 (SQSTM1/p62) gene whose mutations account for most of the sporadic and familial forms of PDB reported in literature. SQSTM1/p62 gene encodes the SQSTM1/p62 protein, component of the NF-kB signaling pathway and mediating intracellular signaling from IL-1/TNF toward NF-kB, crucial for osteoclast differentiation and activity. A functional study suggests that the S Q S T M 1 mutation may predispose to PDB affecting the interaction between SQSTM1/p62 protein and a hitherto unidentified protein(s) modulating the bone turnover, but the underlying molecular mechanism need to be elucidated. However, independently from the knowledge of the functional aspects of S Q S T M 1 / p 6 2 mutation, the opportunity to perform germline mutational analysis in PDB patients may be helpful in detecting new genetic carriers in potentially familial forms of PDB and in studying the co-segregation of such DNA variants with the PDB phenotype. All together these studies could open new possibilities in the prevention and therapy of PDB and of other metabolic bone disorder