SREBP2 restricts osteoclast differentiation and activity by regulating IRF7 and limits inflammatory bone erosion.

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-08-27 DOI:10.1038/s41413-024-00354-4
Haemin Kim, In Ah Choi, Akio Umemoto, Seyeon Bae, Kaichi Kaneko, Masataka Mizuno, Eugenia Giannopoulou, Tania Pannellini, Liang Deng, Kyung-Hyun Park-Min
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Abstract

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.

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SREBP2 通过调节 IRF7 限制破骨细胞的分化和活性,并限制炎性骨侵蚀。
破骨细胞是多核骨吸收细胞,其形成受到严格调控,以防止骨质过度流失。然而,限制破骨细胞形成的机制仍未完全确定。在这里,我们发现固醇调节元件结合蛋白 2(SREBP2)是破骨细胞形成和炎性骨质流失的负调控因子。胆固醇和 SREBP2(胆固醇生物合成的关键转录因子)在破骨细胞形成的晚期增加。在骨髓细胞中消减 SREBP2 会导致体内和体外破骨细胞生成增加,从而导致骨量降低。此外,在小鼠炎性骨溶解和关节炎模型中,SREBP2 的缺失会加速炎性骨破坏。SREBP2 介导的破骨细胞生成调控与其在胆固醇生物合成中的典型功能无关,而是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 调节回路在破骨细胞分化过程中作为负反馈环路所发挥的先前未曾描述过的作用,并代表了一种抑制病理性骨破坏的新机制。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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