title: New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget's disease of bone.
abstract: Paget's disease of bone (PDB) is characterized by focal areas of aberrant and excessive bone turnover, specifically increased bone resorption and disorganized bone formation. Germline mutations in the sequestosome 1/p62 (SQSTM1/p62) gene are common in PDB patients, with most mutations affecting the ubiquitin-associated domain of the protein. In vitro, osteoclast precursor cells expressing PDB-mutant SQSTM1/p62 protein are associated with increases in nuclear factor κB activation, osteoclast differentiation, and bone resorption. Although the precise mechanisms by which SQSTM1/p62 mutations contribute to disease pathogenesis and progression are not well defined, it is apparent that as well as affecting nuclear factor κB signaling, SQSTM1/p62 is a master regulator of ubiquitinated protein turnover via autophagy and the ubiquitin-proteasome system. Additional roles for SQSTM1/p62 in the oxidative stress-induced Keap1/Nrf2 pathway and in caspase-mediated apoptosis that were recently reported are potentially relevant to the pathogenesis of PDB. Thus, SQSTM1/p62 may serve as a molecular link or switch between autophagy, apoptosis, and cell survival signaling. The purpose of this review is to outline recent advances in understanding of the multiple pathophysiological roles of SQSTM1/p62 protein, with particular emphasis on their relationship to PDB, including challenges associated with translating SQSTM1/p62 research into clinical diagnosis and treatment.
authors.affiliation: Department of Endocrinology and Diabetes, Level 1, C Block, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009, Australia. sarah.rea@waimr.uwa.edu.au
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rea
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.forename: Robert
authors.initials: R
authors.lastname: Layfield
authors.forename: Thomas
authors.initials: T
authors.lastname: Ratajczak
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002470:Cell Survival; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D010001:Osteitis Deformans / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D010010:Osteoclasts / Q000378:metabolism*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053245:RANK Ligand; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6; C505688:TNFSF11 protein, human; D057149:Ubiquitinated Proteins; D046988:Proteasome Endopeptidase Complex