The STING inhibitor C‐176 attenuates osteoclast‐related osteolytic diseases by inhibiting osteoclast differentiation

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.

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