Elevated osteoclast (OC) activity is a major contributor to inflammatory bone loss (IBL) during chronic inflammatory diseases. However, the specific OC precursors (OCPs) responding to inflammatory cues and the underlying mechanisms leading to IBL are poorly understood. We identified two distinct OCP subsets: Ly6C^hiCD11b^hi inflammatory OCPs (iOCPs) induced during chronic inflammation, and homeostatic Ly6C^hiCD11b^lo OCPs (hOCPs) which remained unchanged. Functional and proteomic characterization revealed that while iOCPs were rare and displayed low osteoclastogenic potential under normal conditions, they expanded during chronic inflammation and generated OCs with enhanced activity. In contrast, hOCPs were abundant and manifested high osteoclastogenic potential under normal conditions but generated OCs with low activity and were unresponsive to the inflammatory environment. Osteoclasts derived from iOCPs expressed higher levels of resorptive and metabolic proteins than those generated from hOCPs, highlighting that different osteoclast populations are formed by distinct precursors. We further identified the TNF-α and S100A8/A9 proteins as key regulators that control the iOCP response during chronic inflammation. Furthermore, we demonstrated that the response of iOCPs but not that of hOCPs was abrogated in tnf-α^−/− mice, in correlation with attenuated IBL. Our findings suggest a central role for iOCPs in IBL induction. iOCPs can serve as potential biomarkers for IBL detection and possibly as new therapeutic targets to combat IBL in a wide range of inflammatory conditions.

破骨细胞 (OC) 活性升高是慢性炎症性疾病期间炎症性骨丢失 (IBL) 的主要贡献者。然而，对炎症信号响应的特定 OC 前体 (OCP) 以及导致 IBL 的潜在机制知之甚少。我们确定了两个不同的 OCP 子集：Ly6C ^hi CD11b ^hi炎症性 OCP (iOCPs) 在慢性炎症期间诱导，以及稳态 Ly6C ^hi CD11b ^loOCPs (hOCPs) 保持不变。功能和蛋白质组学特征表明，虽然 iOCP 很少见，并且在正常条件下显示出低破骨细胞生成潜力，但它们在慢性炎症期间会扩张并产生活性增强的 OC。相比之下，hOCPs 丰富，在正常条件下表现出高破骨细胞生成潜力，但产生的 OCs 活性低，对炎症环境无反应。来自 iOCPs 的破骨细胞比从 hOCPs 产生的破骨细胞表达更高水平的吸收和代谢蛋白，这突出表明不同的破骨细胞群是由不同的前体形成的。我们进一步确定了 TNF-α 和 S100A8/A9 蛋白是控制慢性炎症期间 iOCP 反应的关键调节因子。此外，tnf-α ^-/-小鼠，与减弱的 IBL 相关。我们的研究结果表明 iOCP 在 IBL 诱导中的核心作用。iOCPs 可以作为 IBL 检测的潜在生物标志物，并可能作为新的治疗靶点在广泛的炎症条件下对抗 IBL。