ArticleArthritis and rheumatism2009
Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling.
Article in Arthritis and rheumatism, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- Growth arrest and DNA damage-inducible 45: a new player on inflammatory diseases.Frontiers in immunology · 2025Review
- Developing the new diagnostic model by integrating bioinformatics and machine learning for osteoarthritis.Journal of orthopaedic surgery and research · 2024Article
- Synoviocytes assist in modulating the effect of Ross River virus infection in micromass-cultured primary human chondrocytes.Journal of medical microbiology · 2024Article
- Gadd45 Proteins in Immunity 2.0.Advances in experimental medicine and biology · 2022Article
- Genetic Parameter Estimation and Whole Sequencing Analysis of the Genetic Architecture of Chicken Keel Bending.Frontiers in genetics · 2022Article
- The role of Gadd45b in neurologic and neuropsychiatric disorders: An overview.Frontiers in molecular neuroscience · 2022Review
- Unbiased transcriptome mapping and modeling identify candidate genes and compounds of osteoarthritis.Frontiers in pharmacology · 2022Article
- Growth arrest and DNA damage-inducible proteins (GADD45) in psoriasis.Scientific reports · 2021Article
- Co-culture with synovial tissue in patients with rheumatoid arthritis suppress cell proliferation by regulating MAPK pathway in osteoblasts.American journal of translational research · 2019Article
- Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription CofactorJournal of immunology (Baltimore, Md. : 1950) · 2017Article
- Th2 and eosinophil responses suppress inflammatory arthritis.Nature communications · 2016Article
- Higher expression of TNFα-induced genes in the synovium of patients with early rheumatoid arthritis correlates with disease activity, and predicts absence of response to first line therapy.Arthritis research & therapy · 2016Article
- The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast-like Synoviocytes.Arthritis & rheumatology (Hoboken, N.J.) · 2015Article
- An overview of animal models of pain: disease models and outcome measures.The journal of pain · 2013Review
- Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis.Arthritis and rheumatism · 2013Article
- Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors.Nature reviews. Rheumatology · 2013Review
- Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway.Arthritis research & therapy · 2012Article
- c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases.The open rheumatology journal · 2012Article
- Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45β-deficient mice.Arthritis and rheumatism · 2011Article
- Molecular targets of natural health products in arthritis.Arthritis research & therapy · 2011Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
objectiveJNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45beta, which is an NF-kappaB-regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45beta expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45beta deficiency increases arthritis severity in passive K/BxN murine arthritis.
methodsActivation of the NF-kappaB and JNK pathways and Gadd45beta expression were analyzed in human synovium and fibroblast-like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45beta(-/-) and wild-type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed.
resultsExpression levels of the Gadd45beta gene and protein were unexpectedly low in human RA synovium despite abundant NF-kappaB activity. Forced Gadd45beta expression in human FLS attenuated tumor necrosis factor-induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45beta deficiency exacerbated K/BxN serum-induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevated MMP3 and MMP13 gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts.
conclusionDeficient Gadd45beta expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45beta expression or by inhibiting the activity of JNK or its upstream regulator, MKK-7.
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