Objectives How 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 the Ripk2104Asp disease allele is sufficient to account for the familial phenotype, we determined the effect of the allele on mice.
Methods Genomic 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-associated RIPK2 (p.Asn104Asp) allele into the genome of inbred mice. The consequences of the Ripk2104Asp disease allele on physiology and OA susceptibility in mice were measured by histology, immunohistochemistry, serum cytokine levels and gene expression.
Results We 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. The Ripk2104Asp allele acts dominantly to alter basal physiology and response to trauma in the mouse knee. Whereas the knees of uninjured Ripk2Asp104 mice appear normal histologically, the joints exhibit a set of marked gene expression changes reminiscent of overt OA. Although the Ripk2104Asp mice lack evidence of chronically elevated systemic inflammation, they do exhibit significantly increased susceptibility to post-traumatic OA (PTOA).
Conclusions Two types of data support the hypothesis that altered NOD/RIPK2 signalling confers susceptibility to OA.
- polymorphism, genetic
- arthritis, experimental
Data availability statement
Data are available upon reasonable request.
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Handling editor Josef S Smolen
Contributors MJJ is responsible for the overall content as the guarantor. MJJ and DJG conceived and designed the study, analysed data and wrote the manuscript. CMG and NHK conceived and designed the study and analysed data. MH, YM, SRV, KAN and KH analysed data and provided feedback on the manuscript.
Funding This work was funded by the Skaggs Foundation for Research (MJJ and NHK), the Utah Genome Project (MJJ, NHK, DJG) the Arthritis National Research Foundation (MJJ—707634), and the National Institute on Ageing (MJJ and DJG—R21AG063534-01A1).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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