NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility.

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.

Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort.

PURPOSE: Our goals were to identify individuals who required surgery for thumb carpometacarpal (CMC) joint osteoarthritis (OA), determine if CMC joint OA clusters in families, define the magnitude of familial risk of CMC joint OA, identify risk factors associated with CMC joint OA, and identify rare genetic variants that segregate with familial CMC joint OA. METHODS: We searched the Utah Population Database to identify a cohort of CMC joint OA patients who required surgery. Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of CMC joint OA. Cox regression models were used to calculate familial risk of CMC joint OA in related individuals. Risk factors were evaluated using logistic regression models. Whole exome sequencing was used to identify rare coding variants associated with familial CMC joint OA. RESULTS: We identified 550 pedigrees with excess clustering of severe CMC joint OA. The relative risk of CMC joint OA requiring surgical treatment was elevated significantly in first- and third-degree relatives of affected individuals, and significant associations with advanced age, female sex, obesity, and tobacco use were observed. We discovered candidate genes that dominantly segregate with severe CMC joint OA in 4 independent families, including a rare variant in Chondroitin Sulfate Synthase 3 (CHSY3). CONCLUSIONS: Familial clustering of severe CMC joint OA was observed in a statewide population. Our data indicate that genetic and environmental factors contribute to the disease process, further highlighting the multifactorial nature of the disease. Genomic analyses suggest distinct biological processes are involved in CMC joint OA pathogenesis. CLINICAL RELEVANCE: Awareness of associated comorbidities may guide the diagnosis of CMC joint OA in at-risk populations and help identify individuals who may not do well with nonoperative treatment. Further pursuit of the genes associated with severe CMC joint OA may lead to assays for detection of early stages of disease and have therapeutic potential.

PIEZO1 variants that reduce open channel probability are associated with familial osteoarthritis.

The synovial joints senses and responds to a multitude of physical forces to maintain joint homeostasis. Disruption of joint homeostasis results in development of osteoarthritis (OA), a disease characterized by loss of joint space, degeneration of articular cartilage, remodeling of bone and other joint tissues, low-grade inflammation, and pain. How changes in mechanosensing in the joint contribute to OA susceptibility remains elusive. PIEZO1 is a major mechanosensitive cation channel in the joint directly regulated by mechanical stimulus. To test whether altered PIEZO1 channel activity causes increased OA susceptibility, we determined whether variants affecting PIEZO1 are associated with dominant inheritance of age-associated familial OA. We identified four rare coding variants affecting PIEZO1 that are associated with familial hand OA. Single channel analyses demonstrated that all four PIEZO1 mutant channels act in a dominant-negative manner to reduce the open probability of the channel in response to pressure. Furthermore, we show that a GWAS mutation in PIEZO1 associated with reduced joint replacement results in increased channel activity when compared with WT and the mutants. Our data support the hypothesis that reduced PIEZO1 activity confers susceptibility to age-associated OA whereas increased PIEZO1 activity may be associated with reduced OA susceptibility.

Familial Clustering of Erosive Hand Osteoarthritis in a Large Statewide Cohort.

OBJECTIVE: Erosive hand osteoarthritis (OA) is a severe and rapidly progressing subset of hand OA. Its etiology remains largely unknown, which has hindered development of successful treatments. This study was undertaken to test the hypothesis that erosive hand OA demonstrates familial clustering in a large statewide population linked to genealogical records, and to determine the association of potential risk factors with erosive hand OA. METHODS: Patients diagnosed as having erosive hand OA were identified by searching 4,741,840 unique medical records from a comprehensive statewide database, the Utah Population Database (UPDB). Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of erosive hand OA as defined by a familial standardized incidence ratio (FSIR) of ≥2.0. The magnitude of familial risk of erosive hand OA in related individuals was calculated using Cox regression models. Association of potential erosive hand OA risk factors was analyzed using multivariate conditional logistic regression and logistic regression models. RESULTS: We identified 703 affected individuals linked to 240 unrelated high-risk pedigrees with excess clustering of erosive hand OA (FSIR ≥2.0, P < 0.05). The relative risk of developing erosive hand OA was significantly elevated in first-degree relatives (P < 0.001). There were significant associations between a diagnosis of erosive hand OA and age, sex, diabetes, and obesity (all P < 0.05). CONCLUSION: Familial clustering of erosive hand OA observed in a statewide database indicates a potential genetic contribution to the etiology of the disease. Age, sex, diabetes, and obesity are risk factors for erosive hand OA. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to erosive hand OA onset and progression.