The unfolded protein response and its relevance to connective tissue diseases
Open accessAbstract
The unfolded protein response (UPR) has evolved to counter the stresses that occur in the endoplasmic reticulum (ER) as a result of misfolded proteins. This sophisticated quality control system attempts to restore homeostasis through the action of a number of different pathways that are coordinated in the first instance by the ER stress-senor proteins IRE1, ATF6 and PERK. However, prolonged ER-stress-related UPR can have detrimental effects on cell function and, in the longer term, may induce apoptosis. Connective tissue cells such as fibroblasts, osteoblasts and chondrocytes synthesise and secrete large quantities of proteins and mutations in many of these gene products give rise to heritable disorders of connective tissues. Until recently, these mutant gene products were thought to exert their effect through the assembly of a defective extracellular matrix that ultimately disrupted tissue structure and function. However, it is now becoming clear that ER stress and UPR, because of the expression of a mutant gene product, is not only a feature of, but may be a key mediator in the initiation and progression of a whole range of different connective tissue diseases. This review focuses on ER stress and the UPR that characterises an increasing number of connective tissue diseases and highlights novel therapeutic opportunities that may arise.
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ER stress is a mechanism involved in the pathogenesis of a range of systemic diseases including connective tissue disorders.
“increasing observations indicate ER stress as a mechanism involved in the pathogenesis of a range of systemic diseases including connective tissue disorders [56–59]”
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References 110 · Cited by 143
- Authors
- Boot-Handford, R. P., & Briggs, M. D.
- Affiliations
- Wellcome Centre for Cell-Matrix Research (GB)
- Corresponding author
- Briggs, Michael D.
- ORCID
- Briggs, Michael D.
- Venue
- Cell and Tissue Research
- Published
- 2009-10-23
- Volume
- 339
- Issue
- 1
- Pages
- 197-211
- ISSN
- 0302-766X (ISSN-L)
- 1432-0878
- PMC
- PMC2784867
- OpenAlex
- W2016131399
- Cited by
- 143
- References
- 110
- Citations by year
- 2026: 4 · 2025: 6 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 10 · 2018: 14 · 2017: 10 · 2016: 8 · 2015: 12 · 2014: 9 · 2013: 9 · 2012: 9
- FWCI
- 0.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell and Tissue Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (084353, LSHM-CT-2007-037471, 084353/Z/07/, RO1 AR49547-01, 084353/B/07/Z, 084353Z/07/Z)
- National Institutes of Health (084353/Z/07/Z, LSHM-CT-2007-037471)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR49547-01, R01AR049547)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- unfolded protein response, endoplasmic reticulum stress, connective tissue diseases, IRE1, ATF6, PERK, protein misfolding, fibroblasts, osteoblasts, chondrocytes, extracellular matrix, hereditary connective tissue disorders, apoptosis, therapeutic target
- MeSH terms
- Animals, Connective Tissue Diseases, Endoplasmic Reticulum, Endoribonucleases, Fibroblasts, Gene Expression Regulation, Homeostasis, Humans, Membrane Proteins, Osteoblasts, Apoptosis, Protein Serine-Threonine Kinases, eIF-2 Kinase, Chondrocytes, Activating Transcription Factor 6, Unfolded Protein Response
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