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Published on: October 20, 2023
A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis
Michael J Jurynec1, Allen D Sawitzke2, Timothy C Beals1
1Department of Orthopaedics, University of Utah, Salt Lake City, 84112, USA.
Abstract:
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.
Insights
Inflammation may drive osteoarthritis (OA) development. A rare RIPK2 gene variant causing an overactive immune response was linked to early-onset OA in a family, suggesting inflammation as a key risk factor.
Area of Science:
- Genetics and Molecular Biology
- Immunology
- Rheumatology
Background:
- Osteoarthritis (OA) is a degenerative joint disease with poorly understood molecular drivers.
- While inflammation is linked to OA, its role in disease onset is debated.
- Limited understanding of OA pathogenesis hinders the development of effective therapeutics.
Purpose of the Study:
- To investigate the genetic and molecular basis of early-onset osteoarthritis.
- To explore the role of inflammation as a potential driver of OA initiation.
- To identify novel therapeutic targets for OA.
Main Methods:
- Family-based genetic analysis to identify causative variants.
- Functional studies in zebrafish embryos to assess protein activity.
- Analysis of gene expression related to OA and inflammation.
Main Results:
- A rare RIPK2 variant (p.Asn104Asp) associated with dominant, early-onset OA was identified.
- The variant RIPK2 protein demonstrated hyperactivity, enhancing innate immune response and NF-κB signaling.
- Upregulation of OA-associated genes was observed due to the hyperactive RIPK2.
- A second RIPK2 allele linked to inflammatory arthritis also showed enhanced NF-κB pathway activity.
Conclusions:
- The inflammatory response, mediated by RIPK2 signaling, can act as a gatekeeper risk factor for osteoarthritis.
- Aberrant RIPK2 activity contributes to OA pathogenesis by promoting inflammation and associated gene expression.
- These findings offer new insights into OA etiology and potential therapeutic strategies targeting inflammatory pathways.
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