Osteoclasts are multinucleated bone-resorbing cells, and their formation is tightly regulated to prevent excessive bone loss. However, the mechanisms by which osteoclast formation is restricted remain incompletely determined. Here, we found that sterol regulatory element binding protein 2 (SREBP2) functions as a negative regulator of osteoclast formation and inflammatory bone loss. Cholesterols and SREBP2, a key transcription factor for cholesterol biosynthesis, increased in the late phase of osteoclastogenesis. The ablation of SREBP2 in myeloid cells resulted in increased in vivo and in vitro osteoclastogenesis, leading to low bone mass. Moreover, deletion of SREBP2 accelerated inflammatory bone destruction in murine inflammatory osteolysis and arthritis models. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor 7 (IRF7). Taken together, our study highlights a previously undescribed role of the SREBP2-IRF7 regulatory circuit as a negative feedback loop in osteoclast differentiation and represents a novel mechanism to restrain pathological bone destruction.

破骨细胞是多核骨吸收细胞，其形成受到严格调节，以防止过度骨质流失。然而，限制破骨细胞形成的机制仍未完全确定。在这里，我们发现甾醇调节元件结合蛋白 2 (SREBP2) 作为破骨细胞形成和炎症性骨质流失的负调节因子。胆固醇和 SREBP2（胆固醇生物合成的关键转录因子）在破骨细胞生成的后期增加。骨髓细胞中 SREBP2 的消除导致体内和体外破骨细胞生成增加，导致骨量降低。此外，SREBP2 的缺失加速了小鼠炎症性骨溶解和关节炎模型中的炎症性骨破坏。 SREBP2 介导的破骨细胞生成调节与其在胆固醇生物合成中的典型功能无关，但部分由其下游靶标干扰素调节因子 7 (IRF7) 介导。综上所述，我们的研究强调了 SREBP2-IRF7 调节回路作为破骨细胞分化中负反馈回路的先前未描述的作用，并代表了一种抑制病理性骨破坏的新机制。