A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis
| Autor: | Brith Otterud, Timothy C. Beals, Mark Leppert, Michael J. Redd, David Grunwald, Jeff Stevens, Michael J. Jurynec, Allen D. Sawitzke |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Arthritis 0302 clinical medicine Orthopedics and Sports Medicine Age of Onset Zebrafish Genetics (clinical) biology Association Studies Articles NF-kappa B General Medicine Corrigenda Receptor-Interacting Protein Serine-Threonine Kinases HMG-CoA reductase Female medicine.symptom Signal transduction Adult medicine.medical_specialty Biomedical Engineering Inflammation Proinflammatory cytokine RIPK2 03 medical and health sciences Chondrocytes Rheumatology Downregulation and upregulation Receptor-Interacting Protein Serine-Threonine Kinase 2 Molecular genetics Osteoarthritis Exome Sequencing Genetics medicine Animals Humans Allele Molecular Biology Alleles 030203 arthritis & rheumatology Innate immune system business.industry Transcription Factor RelA Zebrafish Proteins medicine.disease 030104 developmental biology Amino Acid Substitution Immunology biology.protein Early onset osteoarthritis business |
| Popis: | Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA. |
| Databáze: | OpenAIRE |
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