A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis

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.