NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility

Abstract

ObjectivesHow inflammatory signalling contributes to osteoarthritis (OA) susceptibility is undetermined. An allele encoding a hyperactive form of the Receptor Interacting Protein Kinase 2 (RIPK2) proinflammatory signalling intermediate has been associated with familial OA. To test whether altered nucleotide-binding oligomerisation domain (NOD)/RIPK2 pathway activity causes heightened OA susceptibility, we investigated whether variants affecting additional pathway components are associated with familial OA. To determine whether theRipk2104Aspdisease allele is sufficient to account for the familial phenotype, we determined the effect of the allele on mice.MethodsGenomic analysis of 150 independent families with dominant inheritance of OA affecting diverse joints was used to identify coding variants that segregated strictly with occurrence of OA. Genome editing was used to introduce the OA-associatedRIPK2(p.Asn104Asp) allele into the genome of inbred mice. The consequences of theRipk2104Aspdisease allele on physiology and OA susceptibility in mice were measured by histology, immunohistochemistry, serum cytokine levels and gene expression.ResultsWe identified six novel variants affecting components of the NOD/RIPK2 inflammatory signalling pathway that are associated with familial OA affecting the hand, shoulder or foot. TheRipk2104Aspallele acts dominantly to alter basal physiology and response to trauma in the mouse knee. Whereas the knees of uninjuredRipk2Asp104mice appear normal histologically, the joints exhibit a set of marked gene expression changes reminiscent of overt OA. Although theRipk2104Aspmice lack evidence of chronically elevated systemic inflammation, they do exhibit significantly increased susceptibility to post-traumatic OA (PTOA).ConclusionsTwo types of data support the hypothesis that altered NOD/RIPK2 signalling confers susceptibility to OA.