Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses.
Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses.
复制标题
髋关节骨关节炎患者滑膜成纤维细胞和滑液中的差异代谢型支持炎症反应。
DOI：
10.3390/ijms23063266
复制
发表时间：
2022-03-17
影响因子：
5.6
通讯作者：
Jones SW
中科院分区：
文献类型：
--
作者：
Farah H;Wijesinghe SN;Nicholson T;Alnajjar F;Certo M;Alghamdi A;Davis ET;Young SP;Mauro C;Jones SW
在包括肺纤维化、肾脏疾病和类风湿性关节炎等多种慢性炎症性疾病中，细胞代谢的变化与介导成纤维细胞活化表型有关。因此，本研究旨在描绘一组肥胖和正常体重的髋关节骨关节炎（OA）患者在基础状态和炎症状态下，滑膜关节液和滑膜成纤维细胞的代谢特征。此外，我们试图确定对OA滑膜成纤维细胞中某一代谢途径进行调节是否能改变其炎症活性。滑膜和滑膜液取自正在接受择期关节置换手术的髋关节OA患者，这些患者分为正常体重和肥胖两类。通过1H核磁共振光谱法测定滑膜液代谢组。利用海马XF分析仪，通过乳酸分泌、耗氧率（OCR）和细胞外酸化率（ECAR）来描绘体外分离的滑膜成纤维细胞的代谢特征。评估一种针对谷氨酰胺酶 - 1（GLS1）的小分子药物抑制剂和小干扰RNA（siRNA）的作用，以探究谷氨酰胺代谢在OA滑膜成纤维细胞功能中的作用。与正常体重患者（n = 6）的滑膜液相比，肥胖OA患者（n = 5）的滑膜液呈现出不同的代谢型，1,3 - 二甲基尿酸、N - 亚硝基二甲胺、琥珀酸盐、酪氨酸、丙酮酸盐、葡萄糖、甘氨酸和乳酸盐水平显著升高，且谷氨酰胺 - 谷氨酸代谢途径富集，这与肥胖程度增加相关。在体外，与正常体重患者的成纤维细胞相比，分离出的肥胖OA成纤维细胞在基础状态下乳酸分泌和有氧糖酵解水平更高，在用促炎细胞因子肿瘤坏死因子α（TNFα）刺激时线粒体呼吸增强。抑制GLS1可减弱TNFα诱导的OA滑膜成纤维细胞中白细胞介素 - 6（IL - 6）的表达和分泌。这些研究结果表明，细胞代谢改变是OA成纤维细胞炎症表型的基础，而靶向抑制谷氨酰胺 - 谷氨酸代谢可能为减轻肥胖OA患者关节炎症的病理影响提供一条途径。
Changes in cellular metabolism have been implicated in mediating the activated fibroblast phenotype in a number of chronic inflammatory disorders, including pulmonary fibrosis, renal disease and rheumatoid arthritis. The aim of this study was therefore to characterise the metabolic profile of synovial joint fluid and synovial fibroblasts under both basal and inflammatory conditions in a cohort of obese and normal-weight hip OA patients. Furthermore, we sought to ascertain whether modulation of a metabolic pathway in OA synovial fibroblasts could alter their inflammatory activity. Synovium and synovial fluid was obtained from hip OA patients, who were either of normal-weight or obese and were undergoing elective joint replacement surgery. The synovial fluid metabolome was determined by 1H NMR spectroscopy. The metabolic profile of isolated synovial fibroblasts in vitro was characterised by lactate secretion, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XF Analyser. The effects of a small molecule pharmacological inhibitor and siRNA targeted at glutaminase-1 (GLS1) were assessed to probe the role of glutamine metabolism in OA synovial fibroblast function. Obese OA patient synovial fluid (n = 5) exhibited a different metabotype, compared to normal-weight patient fluid (n = 6), with significantly increased levels of 1, 3-dimethylurate, N-Nitrosodimethylamine, succinate, tyrosine, pyruvate, glucose, glycine and lactate, and enrichment of the glutamine–glutamate metabolic pathway, which correlated with increasing adiposity. In vitro, isolated obese OA fibroblasts exhibited greater basal lactate secretion and aerobic glycolysis, and increased mitochondrial respiration when stimulated with pro-inflammatory cytokine TNFα, compared to fibroblasts from normal-weight patients. Inhibition of GLS1 attenuated the TNFα-induced expression and secretion of IL-6 in OA synovial fibroblasts. These findings suggest that altered cellular metabolism underpins the inflammatory phenotype of OA fibroblasts, and that targeted inhibition of glutamine–glutamate metabolism may provide a route to reducing the pathological effects of joint inflammation in OA patients who are obese.
登录
查看更多内容
影响因子：
4.7
作者：
Christensen R;Henriksen M;Leeds AR;Gudbergsen H;Christensen P;Sørensen TJ;Bartels EM;Riecke BF;Aaboe J;Frederiksen R;Boesen M;Lohmander LS;Astrup A;Bliddal H
通讯作者：
Bliddal H
影响因子：
4.6
作者：
Pearson MJ;Herndler-Brandstetter D;Tariq MA;Nicholson TA;Philp AM;Smith HL;Davis ET;Jones SW;Lord JM
通讯作者：
Lord JM
影响因子：
--
作者：
Avagliano A;Granato G;Ruocco MR;Romano V;Belviso I;Carfora A;Montagnani S;Arcucci A
通讯作者：
Arcucci A
影响因子：
13.3
作者：
de Lange-Brokaar, B. J. E.;Ioan-Facsinay, A.;Kloppenburg, M.
通讯作者：
Kloppenburg, M.
影响因子：
7
作者：
Jones, S. W.;Brockbank, S. M. V.;Newham, P.
通讯作者：
Newham, P.