Can circulating bile acids predict knee OA progression?

循环胆汁酸能预测膝关节OA进展吗？ 骨关节炎（OA）是关节炎最常见的形式。生物标记物可以预测具有类似 风险因素的进展是一个未满足的需求。越来越多的证据表明OA的进展是介导的 通过低度全身性（肥胖）和局部（发炎的滑膜）炎症。最近，一个积极的相关性 血清脂多糖（LPS），微生物组的关键促炎产物，肥胖，关节炎， 炎症和OA严重程度的影响，并表明微生物组和肠道通透性的影响， OA的发病机制。然而，低度炎症介质在多大程度上可以预测OA 进展尚不清楚。 曾经只知道它们在营养吸收中的作用，初级胆汁酸（BA），如鹅去氧胆酸和 胆酸和二级BA，如脱氧胆酸和石胆酸，是产生的信号分子， 通过宿主和肠道微生物群的相互作用， 磁导率这些生物活性代谢物作用于在先天性巨噬细胞中高度表达的几种受体。 免疫力它们调节多种细胞类型和组织中的多种代谢和炎症途径。 重要的是，人类肥胖与BA代谢改变和肠通透性增加有关。 我们在膝关节OA（KOA）受试者中的初步研究表明，循环BA与 放射学KOA和结局评分。最显著的相关性是胆酸， 与西安大略和麦克马斯特大学骨关节炎指数（WOMAC）相关（r=0.44，p=0.01）。 有趣的是，BA也与滑膜炎（甘氨熊去氧胆酸，r=0.39，p=0.04）和LPS相关。 结合蛋白（LBP），KOA进展的生物标志物（胆酸，r=0.41，p=0.03）。有趣的是，这些 肥胖和非肥胖受试者之间的相关性不同。这些观察结果表明，不同的BA可能是 OA发展和进展的关键介质。 因此，我们假设（1）BA谱与KOA的MRI表型相关，尤其是与 滑膜炎/积液; 2）BA谱改变与KOA进展相关。为了实现这一目标，我们将 在仔细分型的FNIH/OAI生物标志物项目队列中进行我们的研究， 48个月时的半定量和定量MRI评分以及临床和影像学结局， OAI网站，将循环BAs与滑膜炎和KOA进展联系起来。建议的实验是 高风险，我们将确定1）特定循环BA是否与滑膜炎和KOA相关2）定义元素 脂质发病机制，联系KOA的结果在所有的人之间的风险。然而，这些研究可能会提供一个 基金会确定KOA的表型和研究新的个性化干预措施，以减少 与KOA相关的发病率。

Can Circulating Bile Acids Predict Knee OA Progression? Osteoarthritis (OA) is the most common form of arthritis. Biomarkers that could predict the individuals with similar risk factors that would progress is an unmet need. Increasing evidence indicates that OA progression is mediated by low-grade systemic (obesity) and local (inflamed synovium) inflammation. Recently, a positive correlation between serum lipopolysaccharide (LPS), a key proinflammatory product of the microbiome, obesity, joint inflammation, and OA severity was reported and suggests an influence of microbiome and gut permeability in the pathogenesis of OA. However, the extent to which low-grade inflammation-based mediators can predict OA progression remains unclear. Once known only for their role in nutrients absorption, primary bile acids (BAs) such as chenodeoxycholic and cholic acid, and secondary BAs, such as deoxycholic and lithocholic acid, are signaling molecules generated from cholesterol breakdown by the interaction of the host and intestinal microbiota that modulate intestinal permeability. These bioactive metabolites act on several receptors that are highly expressed in cells of innate immunity. They regulate diverse metabolic and inflammatory pathways in multiple cell types and tissues. Importantly, human obesity is associated with altered BA metabolism and increased intestinal permeability. Our preliminary studies in knee OA (KOA) subjects show that circulating BAs are significantly associated with radiographic KOA and outcome scores. The most significant association was for cholic acid, that was significantly associated with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (r=0.44, p=0.01). Interestingly, BAs also associated with synovitis (glycoursodeoxycholic acid, r=0.39, p=0.04), and with LPS binding protein (LBP), a biomarker of KOA progression (cholic acid, r=0.41, p=0.03). Of interest, these associations differed between obese and non-obese subjects. These observations suggest distinct BAs may be key mediators of OA development and progression. Therefore, we hypothesize that (1) BA profiles will be associated with MRI phenotypes of KOA, especially with synovitis/effusion; 2) altered BA profiles are associated with KOA progression. To address this goal, we will conduct our investigation in the carefully phenotyped FNIH/OAI Biomarkers Project cohort, with semiquantitative and quantitative MRI scores and clinical and radiographic outcomes at 48 months available in the OAI website, to relate circulating BAs with synovitis and KOA progression. The proposed experiments are high risk and we will determine if 1) specific circulating BA are related to synovitis and KOA 2) define elements of lipid pathogenesis that link KOA outcomes among all persons at risk. However, these studies might provide a foundation to determine phenotypes of KOA and investigations into novel personalized interventions to reduce KOA-related morbidity.