Inflammatory osteolysis occurs primarily in the context of osteoarthritis, aseptic inflammation, prosthesis loosening, and other conditions. An excessive immune inflammatory response causes excessive activation of osteoclasts, leading to bone loss and bone destruction. The signaling protein stimulator of interferon gene (STING) can regulate the immune response of osteoclasts. C-176 is a furan derivative that can inhibit activation of the STING pathway and exert anti-inflammatory effects. The effect of C-176 on osteoclast differentiation is not yet clear. In this study, we found that C-176 could inhibit STING activation in osteoclast precursor cells and inhibit osteoclast activation induced by nuclear factor κB ligand receptor activator in a dose-dependent manner. After treatment with C-176, the expression of the osteoclast differentiation marker genes nuclear factor of activated T-cells c1(NFATc1), cathepsin K, calcitonin receptor, and V-ATPase a3 decreased. In addition, C-176 reduced actin loop formation and bone resorption capacity. The WB results showed that C-176 downregulated the expression of the osteoclast marker protein NFATc1 and inhibited activation of the STING-mediated NF-κB pathway. We also found that C-176 could inhibit the phosphorylation of mitogen-activated protein kinase signaling pathway factors induced by RANKL. Moreover, we verified that C-176 could reduce LPS-induced bone absorption in mice, reduce joint destruction in knee arthritis induced by meniscal instability, and protect against cartilage matrix loss in ankle arthritis induced by collagen immunity. In summary, our findings demonstrated that C-176 could inhibit the formation and activation of osteoclasts and could be used as a potential therapeutic agent for inflammatory osteolytic diseases.

中文翻译：

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STING 抑制剂 C-176 通过抑制破骨细胞分化减轻破骨细胞相关的溶骨性疾病

炎症性骨质溶解主要发生在骨关节炎、无菌性炎症、假体松动和其他情况下。过度的免疫炎症反应会导致破骨细胞过度活化，从而导致骨质流失和骨质破坏。干扰素基因信号蛋白刺激因子（STING）可以调节破骨细胞的免疫反应。C-176 是一种呋喃衍生物，可以抑制 STING 通路的激活并发挥抗炎作用。C-176 对破骨细胞分化的影响尚不清楚。在这项研究中，我们发现 C-176 可以抑制破骨细胞前体细胞中的 STING 激活，并以剂量​​依赖的方式抑制核因子 κB 配体受体激活剂诱导的破骨细胞激活。用C-176处理后，活化T细胞c1(NFATc1)、组织蛋白酶K、降钙素受体、V-ATP酶a3的破骨细胞分化标志基因核因子表达降低。此外，C-176 减少了肌动蛋白环的形成和骨吸收能力。WB 结果显示，C-176 下调破骨细胞标志蛋白 NFATc1 的表达并抑制 STING 介导的 NF-κB 通路的激活。我们还发现 C-176 可以抑制 RANKL 诱导的丝裂原活化蛋白激酶信号通路因子的磷酸化。此外，我们证实 C-176 可以减少 LPS 诱导的小鼠骨吸收，减少由半月板不稳定引起的膝关节炎的关节破坏，并防止由胶原免疫引起的踝关节炎的软骨基质损失。总之，