New Insights Into the Role of Sequestosome 1/p62 Mutant Proteins in the Pathogenesis of Paget's Disease of Bone
Open accessAbstract
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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Novel optineurin mutations in sporadic amyotrophic lateral sclerosis patients
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A Probable Linkage Between Familial Paget's Disease and the HLA Loci*
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Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees
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Self-citationFailure to Detect Measles Virus Ribonucleic Acid in Bone Cells from Patients with Paget’s Disease
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Perry, J. A., Kiezun, A., Tonzi, P., Van Allen, E. M., Carter, S. L., Baca, S. C., Cowley, G. S., Bhatt, A. S., Rheinbay, E., Pedamallu, C. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1419260111 · Cited by 481 · see citing works
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The overlapping genetics of amyotrophic lateral sclerosis and frontotemporal dementia
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Autophagy and ALS: mechanistic insights and therapeutic implications
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“tin recognition [130], whereas mutations within the LIR domain impact LC3 recognition and substrate delivery to”
BackgroundSQSTM1 mutations – Bridging Paget disease of bone and ALS/FTLD
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Self-citationOsteosarcoma: Molecular Pathogenesis and iPSC Modeling
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Russo, S., Scotto di Carlo, F., Maurizi, A., Fortunato, G., Teti, A., Licastro, D., Settembre, C., Mello, T., & Gianfrancesco, F. (2023) · Bone Research · doi:10.1038/s41413-023-00250-3 · Cited by 11 · see citing works
- 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
- Publisher
- The Endocrine Society
- 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
- Open access
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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