Can circulating bile acids predict knee OA progression?

循环胆汁酸能预测膝骨性关节炎的进展吗？ 骨关节炎(OA)是最常见的关节炎。可以预测具有相似基因的个体的生物标志物 可能取得进展的风险因素是一种未得到满足的需求。越来越多的证据表明，骨性关节炎的进展是通过调节的 由低度全身(肥胖)和局部(滑膜发炎)炎症所致。最近，一个正相关 在微生物组的关键促炎产物--血清脂多糖(LPS)与肥胖、关节 炎症和OA的严重程度被报道，并表明微生物群和肠道通透性在 骨性关节炎的发病机制。然而，低级别炎症介质预测骨性关节炎的程度 进展尚不清楚。 曾经只知道它们在营养吸收中的作用的初级胆汁酸(BA)，如鹅去氧胆酸和 胆酸和次生碱，如脱氧胆酸和石胆酸，是产生的信号分子。 通过宿主和调节肠道的微生物群的相互作用来防止胆固醇的分解 渗透性。这些生物活性代谢物作用于几种受体，这些受体在先天细胞中高度表达 豁免权。它们在多种细胞类型和组织中调节不同的代谢和炎症途径。 重要的是，人类肥胖与BA代谢改变和肠道通透性增加有关。 我们在膝关节骨性关节炎(KOA)受试者中的初步研究表明，循环中的BA与 放射学膝关节骨性关节炎和预后评分。最重要的联系是胆酸，这是显著的 与西安大略省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，bas还与滑膜炎(甘草脱氧胆酸，r=0.39，p=0.04)和内毒素有关 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 肥胖者和非肥胖者之间的联系有所不同。这些观察表明，不同的bas可能是 办公自动化发展和进步的关键调停者。 因此，我们假设(1)BA图谱将与膝关节骨性关节炎的MRI表型相关，尤其是与 滑膜炎/积液；2)BA轮廓改变与KOA的进展有关。为了实现这一目标，我们将 在FNIH/OAI生物标记物项目队列中进行仔细表型的调查，与 半定量和定量的MRI评分以及48个月的临床和放射学结果 OAI网站，将循环基底动脉与滑膜炎和膝关节骨性关节炎进展联系起来。建议的实验是 高风险，我们将确定1)特定的循环BA是否与滑膜炎和膝关节骨性关节炎有关2)确定元素 与所有高危人群的膝关节骨性关节炎结果相联系的脂质致病机制。然而，这些研究可能会提供一个 确定膝骨性关节炎表型的基础和研究新的个性化干预措施以减少 与膝关节骨性关节炎相关的发病率。

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.