Department of Orthopaedics, University of Utah, Salt Lake City, 84112, USA.
Division of Rheumatology, Department of Internal Medicine, University of Utah, Salt Lake City, 84112, USA.
Hum Mol Genet. 2018 Jul 1;27(13):2383-2391. doi: 10.1093/hmg/ddy132.
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-κB 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-κB 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-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.
骨关节炎（OA）是一种常见的使人虚弱的疾病，其特征是关节软骨和骨的异常重塑。由于对影响疾病起始和进展的分子途径的了解有限，因此缺乏改善治疗方法。值得注意的是，尽管炎症与明显的 OA 之间存在关联已得到充分证实，但炎症作为疾病发生的驱动因素仍存在很大争议。我们分析了一个具有早发性 OA 显性遗传的家族，发现受影响的个体携带有一个罕见的变异等位基因，该基因编码在受体相互作用蛋白激酶 2（RIPK2）的激酶结构域中的一个显著的氨基酸变化（p.Asn104Asp），该激酶通过 NF-κB 途径传递来自激活的细菌肽聚糖传感器的信号，以产生促炎免疫反应。对斑马鱼胚胎中 RIPK2 活性的功能分析表明，变异的 RIPK2104Asp 蛋白在其信号转导能力方面具有超活性，增强了激活先天免疫反应和 NF-κB 途径的能力，并促进 OA 相关基因的上调。进一步，我们发现与关节炎相关的另一个与炎症性疾病相关的 RIPK2 等位基因也具有增强的 NF-κB 通路激活活性。我们的研究首次揭示了炎症反应可以作为 OA 的风险因素。
