ArticleThe American journal of pathology2012
D469del-COMP retention in chondrocytes stimulates caspase-independent necroptosis.
Article in The American journal of pathology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 45 citations in OpenAlex.
- Genotype-phenotype correlations in PSACH/EDM1 patients withFrontiers in endocrinology · 2026Review
- Review
- DNA damage-inducible transcript 3 positively regulates RIPK1-mediated necroptosis.Cell death and differentiation · 2025Article
- Loss of CHOP Prevents Joint Degeneration and Pain in a Mouse Model of Pseudoachondroplasia.International journal of molecular sciences · 2024Article
- Significance of Necroptosis in Cartilage Degeneration.Biomolecules · 2024Review
- Curcumin and Resveratrol: Nutraceuticals with so Much Potential for Pseudoachondroplasia and Other ER-Stress Conditions.Biomolecules · 2024Review
- CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia.International journal of molecular sciences · 2023Article
- Anti-Osteoarthritic Effects of Cartilage-Derived Extracellular Matrix in a Rat Osteoarthritis Model.Tissue engineering and regenerative medicine · 2023Article
- Cartilage Oligomeric Matrix Protein, Diseases, and Therapeutic Opportunities.International journal of molecular sciences · 2022Review
- Primary Osteoarthritis Early Joint Degeneration Induced by Endoplasmic Reticulum Stress Is Mitigated by Resveratrol.The American journal of pathology · 2021Article
- Joint Degeneration in a Mouse Model of Pseudoachondroplasia: ER Stress, Inflammation, and Block of Autophagy.International journal of molecular sciences · 2021Article
- Article
- Proteotoxic Stress and Cell Death in Cancer Cells.Cancers · 2020Review
- Cartilage Trauma Induces Necroptotic Chondrocyte Death and Expulsion of Cellular Contents.International journal of molecular sciences · 2020Article
- Novel mTORC1 Mechanism Suggests Therapeutic Targets for COMPopathies.The American journal of pathology · 2019Article
- Mutant cartilage oligomeric matrix protein (COMP) compromises bone integrity, joint function and the balance between adipogenesis and osteogenesis.Matrix biology : journal of the International Society for Matrix Biology · 2018Article
- Zhuangguguanjie formulation protects articular cartilage from degeneration in joint instability-induced murine knee osteoarthritis.American journal of translational research · 2018Article
- Necrostatin-1 Mitigates Endoplasmic Reticulum Stress After Spinal Cord Injury.Neurochemical research · 2017Article
- Review
- Therapeutic potential of NADPH oxidase 1/4 inhibitors.British journal of pharmacology · 2017Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in the cartilage oligomeric matrix protein gene (COMP) cause pseudoachondroplasia (PSACH). This dysplasia results from the intracellular retention of mutant COMP protein and premature death of growth-plate chondrocytes. Toward better understanding of these underlying mechanisms, we examined D469del-COMP activation of the unfolded protein response and cell death pathways in rat chondrosarcoma cells. Using an inducible expression system, we examined the effects of D469del-COMP retention after 4 days of mRNA expression and then 5 days without inducing agent. Retention of D469del-COMP stimulated Chop (Ddit3) and Gadd34 (Ppp1r15a) and triggered reactivation of protein translation that exacerbated intracellular retention. High levels of Nox4 and endoplasmic reticulum receptor stress-inducible Ero1β generated reactive oxygen species, causing oxidative stress. Increased expression of Gadd genes and presence of γH2AX indicated that DNA damage was occurring. The presence of cleaved apoptosis inducing factor (tAIF) and the absence of activated caspases indicated that retention of D469del-COMP triggers cell death in chondrocytes by necroptosis, a caspase-independent programmed necrosis. Loss of growth-plate chondrocytes by necroptosis was also found in our pseudoachondroplasia mouse model. These results suggest a model in which D469del-COMP expression induces persistent endoplasmic reticulum stress, oxidative stress, and DNA damage, thus priming chondrocytes for necroptosis. We define for the first time the precise mechanisms underlying D469del-COMP pathology in pseudoachondroplasia and suggest that oxidative stress and AIF may be promising therapeutic targets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.