Mutations of SQSTM1 occur in about10% of patients with Paget's disease of bone (PDB), but it is unclear whether they play a causal role or regulate susceptibility to an environmental trigger. Here we show that mice with a proline to leucine mutation at codon 394 of mouse sqstm1 (P394L), equivalent to the P392L SQSTM1 mutation in humans, develop a bone disorder with remarkable similarity to PDB. The P394L mutant mice developed focal bone lesions with increasing age and by 12 months, 14/18 (77%) heterozygotes and 20/21 (95%) homozygotes had lesions, compared with 0/18 (0%) wild-type littermates (P< 0. 001). Lesions predominantly affected the lower limbs in an asymmetric manner and were characterized by focal increases in bone turnover, with increased bone resorption and formation, disruption of the normal bone architecture and accumulation of woven bone. Osteoclasts within lesions were larger and more nucleated than normal and some contained nuclear inclusions similar to those observed in human PDB. Osteoclast precursors from P394L mutant mice had increased sensitivity to RANKL in vitro resulting in the generation of osteoclasts that were larger and more nucleated than those generated from wild-type littermates VSports手机版. There was increased expression of sqstm1, autophagy-related gene 5 (atg5) and light chain 3 gene (lc3) in osteoclast precursors and increased LC3-II protein levels in Bafilomycin-treated osteoclasts from P394L mutant mice compared with wild-type suggesting dysregulation of autophagy and enhanced autophagosome formation. These studies demonstrate that SQSTM1 mutations can cause a PDB-like skeletal disorder in the absence of an additional trigger and provide a new disease model for PDB. .