NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility

Area of Science:

• Immunology
• Genetics
• Rheumatology

Background:

• The role of inflammatory signaling in osteoarthritis (OA) susceptibility remains unclear.
• A hyperactive Receptor Interacting Protein Kinase 2 (RIPK2) allele is linked to familial OA.
• Investigating the nucleotide-binding oligomerisation domain (NOD)/RIPK2 pathway's role in OA is crucial.

Purpose of the Study:

• To determine if altered NOD/RIPK2 pathway activity increases OA susceptibility.
• To identify variants in additional pathway components associated with familial OA.
• To assess if the Ripk2 disease allele is sufficient to cause familial OA.

Main Methods:

• Genomic analysis of 150 families with dominant OA inheritance.
• Genome editing to introduce the OA-associated RIPK2 (p.Asn104Asp) allele into mice.
• Assessing OA susceptibility and physiological changes in mice via histology, immunohistochemistry, serum cytokine levels, and gene expression.

Main Results:

• Six novel variants in NOD/RIPK2 pathway components associated with familial OA were identified.
• The Ripk2 allele dominantly affects mouse knee physiology and trauma response.
• Ripk2 mice exhibit OA-like gene expression changes and increased susceptibility to post-traumatic OA (PTOA).

Conclusions:

• Altered NOD/RIPK2 signaling confers susceptibility to osteoarthritis.
• The Ripk2 disease allele is sufficient to induce OA-like changes and increase PTOA susceptibility in mice.