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 Ripk2 104Asp 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 Ripk2 104Asp 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 Ripk2 104Asp allele acts dominantly to alter basal physiology and response to trauma in the mouse knee. Whereas the knees of uninjured Ripk2 Asp104 mice appear normal histologically, the joints exhibit a set of marked gene expression changes reminiscent of overt OA. Although the Ripk2 104Asp 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.

Michael J Jurynec

Catherine M Gavile

Matthew Honeggar

Ying Ma

Shivakumar R Veerabhadraiah

Kendra A Novak

Kazuyuki Hoshijima

Nikolas H Kazmers

David J Grunwald

Annals of the Rheumatic Diseases

风湿病年鉴 (ARD) 是一份国际同行评审期刊，致力于促进最高标准的科学交流和教育。它涵盖了风湿病学的所有方面，包括肌肉骨骼疾病、关节炎疾病和结缔组织疾病的谱系。 ARD 发表基础、临床和转化科学研究。鼓励简明的科学交流，并以同行评审的国际会议论文集为特色。教育论文包括最先进的评论、“如何”文章和教育案例，重点关注临床实践中面临的问题。该杂志于 1939 年首次出版，拥有权威的全球编辑委员会和不断增长的国际读者群。

The Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal dedicated to promoting the highest standards of scientific communication and education. It covers all aspects of rheumatology, including musculoskeletal disorders, arthritic diseases, and connective tissue diseases. ARD publishes basic, clinical, and translational scientific research, encouraging concise scientific communication and featuring peer-reviewed conference proceedings. Educational papers include cutting-edge reviews, 'how-to' articles, and educational cases, focusing on issues faced in clinical practice. Since its first publication in 1939, the journal has maintained a prestigious global editorial board and a growing international readership.

《Annals of the Rheumatic Diseases》（风湿病年鉴，ARD）是一份国际同行评审的学术期刊，旨在促进高标准的科学交流与教育。期刊涵盖风湿病学的各个方面，包括肌肉骨骼疾病、关节炎和结缔组织疾病等。ARD发表基础研究、临床研究和转化科学研究，鼓励简洁明了的科学交流，并定期刊登国际会议的同行评审论文。教育类论文包括前沿评论、实用指南和教育案例，重点关注临床实践中遇到的问题。该杂志自1939年创刊以来，拥有权威的全球编辑委员会和不断扩大的国际读者群。

NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility

Six novel variants affecting components of the NOD/RIPK2 inflammatory signalling pathway that are associated with familial OA affecting the hand, shoulder or foot are identified.

Category	Quartile
医学	1
医学, 风湿病学	1

NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility

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