Institute for Medical Microbiology, Immunology, and Hygiene, Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne and Faculty of Medicine, University of Cologne, 50935 Cologne, Germany.
Department of Orthodontics, University Hospital Regensburg, 93053 Regensburg, Germany.
Cells. 2024 Mar 13;13(6):496. doi: 10.3390/cells13060496.
Osteoarthritis (OA) is a multifactorial disease depending on molecular, genetic, and environmental factors like mechanical strain. Next to the cartilage and the subchondral bone, OA also affects the synovium, which is critically involved in the maintenance of joint homeostasis. As there is a correlation between the extracellular sodium content in the knee joint and OA, this study investigates the impact of sodium on OA-associated processes like inflammation and bone remodeling without and with mechanical loading in synovial fibroblasts. For that purpose, murine synovial fibroblasts from the knee joint were exposed to three different extracellular sodium chloride concentrations (-20 mM, ±0 mM and +50 mM NaCl) in the absence or presence of compressive or intermittent tensile strain. In addition to the intracellular Na content and gene expression of the osmoprotective transcription factor nuclear factor of activated T cells 5 (), the gene and protein expression of inflammatory mediators (interleukin-6 (IL6), prostaglandin endoperoxide synthase-2 ()/prostaglandin E (PGE)), and factors involved in bone metabolism (receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG)) were analyzed by qPCR and ELISA. Mechanical strain already increased intracellular Na and gene expression at standard salt conditions to levels obtained by exposure to increased extracellular Na content. Both high salt and compressive strain resulted in elevated IL6 and PGE release. Intermittent tensile strain did not increase mRNA expression or IL6 protein secretion but triggered expression and PGE production. Increased extracellular Na levels and compressive strain increased RANKL expression. In contrast, intermittent tension suppressed RANKL expression without this response being subject to modification by extracellular sodium availability. OPG expression was only induced by compressive strain. Changes in extracellular Na levels modified the inflammatory response and altered the expression of mediators involved in bone metabolism in cells exposed to mechanical strain. These findings indicate that Na balance and are important players in synovial fibroblast responses to mechanical stress. The integration of Na and Na-dependent signaling will help to improve the understanding of the pathogenesis of osteoarthritis and could lead to the establishment of new therapeutic targets.
骨关节炎（OA）是一种多因素疾病，取决于分子、遗传和环境因素，如机械应变。除了软骨和软骨下骨，OA 还影响滑膜，滑膜在维持关节内稳态方面起着至关重要的作用。由于膝关节中外细胞钠离子含量与 OA 之间存在相关性，因此本研究调查了钠离子对 OA 相关过程的影响，如炎症和骨重塑，同时还研究了在滑膜成纤维细胞中有无机械负荷的情况下钠离子的影响。为此，本研究从膝关节中分离出鼠滑膜成纤维细胞，在无或有压缩或间歇拉伸应变的情况下，将其暴露于三种不同的细胞外氯化钠浓度（-20 mM、±0 mM 和 +50 mM NaCl）下。除了细胞内 Na 含量和核因子激活 T 细胞 5 的转录因子（NFAT5）的基因表达外，还通过 qPCR 和 ELISA 分析了炎症介质（白细胞介素 6（IL6）、前列腺素内过氧化物合酶-2（）/前列腺素 E（PGE））和参与骨代谢的因子（核因子 κB 配体受体激活剂（RANKL）、骨保护素（OPG））的基因和蛋白表达。在标准盐条件下，机械应变已经使细胞内 Na 和 基因表达增加到通过暴露于增加的细胞外 Na 含量获得的水平。高盐和压缩应变均导致 IL6 和 PGE 释放增加。间歇拉伸应变不会增加 mRNA 表达或 IL6 蛋白分泌，但会触发 表达和 PGE 产生。增加细胞外 Na 水平和压缩应变增加了 RANKL 表达。相反，间歇张力抑制了 RANKL 表达，而这种反应不受细胞外 Na 可用性的影响。OPG 表达仅受压缩应变诱导。细胞外 Na 水平的变化改变了暴露于机械应变的细胞中的炎症反应，并改变了参与骨代谢的介质的表达。这些发现表明 Na 平衡和 是滑膜成纤维细胞对机械应激反应的重要参与者。Na 和 Na 依赖性信号的整合将有助于加深对骨关节炎发病机制的理解，并可能为建立新的治疗靶点提供帮助。
