Cited by 123Bone Metabolism and DiseasesAlkaline Phosphatase Research StudiesBone Tumor Diagnosis and Treatments

New Insights Into the Role of Sequestosome 1/p62 Mutant Proteins in the Pathogenesis of Paget's Disease of Bone

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Rea, Sarah L., Walsh, John P., Layfield, Robert, Ratajczak, Thomas, Xu, Jiake·2013·Endocrine Reviews

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.

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Crossref · 10.1210/er.2012-1034

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Authors
Rea, S. L., Walsh, J. P., Layfield, R., Ratajczak, T., & Xu, J.
Affiliations
  • The University of Western Australia (AU)
  • University of Nottingham (GB)
Corresponding author
Rea, Sarah L.
Venue
Endocrine Reviews
Published
2013-08-01
Volume
34
Issue
4
Pages
501-524
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
OpenAlex
W2128142924
Cited by
123
References
264
Citations by year
2026: 8 · 2025: 6 · 2024: 11 · 2023: 13 · 2022: 10 · 2021: 6 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 11 · 2016: 9 · 2015: 10 · 2014: 9 · 2013: 1
FWCI
0.91
Type
journal article
Language
en
Licence
other-oa
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
Funders
Versus Arthritis (18585)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
Keywords
Paget's disease of bone, germline mutations, ubiquitin-associated domain, osteoclastogenesis, bone resorption, NF-κB signaling, autophagy, ubiquitin-proteasome system, Nrf2/Keap1 pathway, oxidative stress, caspase-dependent apoptosis, bone turnover, pathogenesis
MeSH terms
Sequestosome-1 Protein, Animals, Autophagy, Cell Survival, Humans, Models, Biological, Mutation, Osteitis Deformans, Osteoclasts, Signal Transduction, Apoptosis, Oxidative Stress, Proteasome Endopeptidase Complex, TNF Receptor-Associated Factor 6, Adaptor Proteins, Signal Transducing, RANK Ligand, Ubiquitinated Proteins

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