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A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-?B pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-?B pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-?B pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.

SUBMITTER: Jurynec MJ

PROVIDER: S-EPMC6620756 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis.

Jurynec Michael J MJ Sawitzke Allen D AD Beals Timothy C TC Redd Michael J MJ Stevens Jeff J Otterud Brith B Leppert Mark F MF Grunwald David Jonah DJ

Human molecular genetics 20180701 13

Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset ...[more]

PMID: 29659823

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Project description:BackgroundInvestigating the pathophysiological mechanisms of early osteoarthritis (OA) is of utmost interest since this stage holds the strongest promise for therapeutic interventions. The aims of this study were to analyze if synovial inflammation is already present in early OA and to characterize the involved cell populations, by investigating synovial fluid (SF) and synovial membrane (SM) of early OA patients for the presence and polarization status of CD4 T cells.MethodsA quantitative analysis of CD4+ T cell infiltration in SF and SM compared to peripheral blood (PB) was performed in patients with early stages of OA. We further investigated intracellular staining (ICS), surface marker, and chemokine receptor expression profiles of CD4+ T cells in SF, SM, and PB, as well as cytokine expression in native SF and PB. Matched samples of SF, SM, and PB were harvested from 40 patients with early OA at the time of surgery. Early OA was confirmed by independent surgeons intraoperatively. Samples were analyzed by flow cytometry for surface markers and cytokines, which are preferentially expressed by distinct T cell subsets (Th1, Th2, Th17, regulatory T cells). Furthermore, we analyzed native SF and PB supernatants using MACSPlex for multiple cytokine expression profiles.ResultsSF and SM showed a distinct infiltration of CD4+ T lymphocytes, with significantly increased expression of chemokine receptors CXCR3/CCR5, cytokine IFN-γ (preferentially expressed by Th1 cells), and CD161 (preferentially expressed by IL-17 producing Th17 cells) compared to PB. Furthermore, the percentage of CD4+ T cells polarized to Treg was significantly increased in SM compared to SF and PB. No significant differences were observed for CCR3 and CCR4 (preferentially expressed by Th2 cells), although IL-4 values were significantly higher in SM and SF compared to PB. Cytokine analysis showed comparable results between PB and SF, with only IL-6 being significantly increased in SF.ConclusionsEarly OA joints show already significant inflammation through CD4+ T cell infiltration, with predominant Th1 cell polarization. Inflammation seems to be driven by direct proinflammatory cell interaction. Cytokine signaling seems to be negligible at the site of inflammation in early OA, with only IL-6 being significantly increased in SF compared to PB.

Project description:Background & aimsThe incidence of colorectal cancer (CRC) is increasing in individuals younger than 50 years, who do not usually undergo screening if they are of average risk. We sought to identify risk factors for CRC in this population.MethodsWe compared sociodemographic and medical characteristics of patients who received a diagnosis of CRC at an age of 18-49 years (early-onset) with patients who received a diagnosis of CRC at an age of 50 years or older (late-onset) and with age-matched, cancer-free individuals (controls) at a tertiary academic hospital. We collected data from all adult patients with a diagnosis of CRC from January 1, 2011 through April 3, 2017 from electronic health records. Associations with risk factors were assessed using univariable and multivariable logistic regression models.ResultsWe identified 269 patients with early-onset CRC, 2802 with late-onset CRC, and 1122 controls. Compared with controls, patients with early-onset CRC were more likely to be male (odds ratio [OR], 1.87; 95% CI, 1.39-2.51), have inflammatory bowel disease (IBD) (3% vs 0.4% for controls; univariable P < .01), and have a family history of CRC (OR, 8.61; CI, 4.83-15.75). Prevalence values of well-established modifiable CRC risk factors, including obesity, smoking, and diabetes, were similar. Compared to patients with late-onset CRC, patients with early-onset CRC were more likely to be male (OR, 1.44; 95% CI, 1.11-1.87), black (OR, 1.73; 95% CI, 1.08-2.65) or Asian (OR, 2.60; 95% CI, 1.57-4.15), and have IBD (OR, 2.97; 95% CI, 1.16-6.63) or a family history of CRC (OR, 2.87; 95% CI, 1.89-4.25). Sensitivity analyses excluding IBD and family history of CRC showed comparable results. Early-onset CRC was more likely than late-onset disease to be detected in the left colon or rectum (75% vs 59%, P = .02) and at a late stage of tumor development (77% vs 62%, P = .01).ConclusionsIn a retrospective study of patients with early-onset CRC vs late-onset CRC or no cancer, we identified non-modifiable risk factors, including sex, race, IBD, and family history of CRC, to be associated with early-onset CRC.

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A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis.

Publications

A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis.

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