探究IRG1在骨质疏松症中的保护效应及作用机制

Despite the current multi-drug treatment of osteoporosis, the incidence of osteoporotic fractures remains high. Therefore, new effective targets need to be explored to prevent and delay the occurrence and progression of osteoporosis. We have previously confirmed that the expression of Irg1 in patients with osteoporosis was significantly down-regulated compared with normal people. And Irg1 knockout mice (Irg1-/-) exhibited an osteoporosis phenotype. Irg1 can catalyze the synthesis of cellular metabolite itaconate in vivo. Irg1-/-mice were then injected intraperitoneally with exogenous itaconate and we found that their bone loss was significantly rescued. In vitro experiments showed that Irg1 inhibited osteoclast differentiation by regulating the synthesis of itaconate. RNA-seq analysis and ShRNA silencing experiments indicated that itaconate enhanced the expression of G-protein coupled receptor Gpr161 to inhibit the osteoclastogenesis. Therefore, we speculate that Irg1 mainly promotes the synthesis of itaconate, thereby promoting the expression of Gpr161, and plays a protective role in osteoporosis. This project for the first time demonstrates the cell metabolite itaconate was associated with osteoporosis. It is proposed to further verify the protective effect of Irg1 in osteoporosis by constructing a normal mouse osteoporosis model and confirm the interaction between itaconate and Gpr161 using aequorin assay. We intend to provide a theoretical basis for clarifying the pathogenesis of osteoporosis and treating osteoporosis.

尽管目前有多种药物治疗骨质疏松症，但是骨质疏松性骨折的发病率依旧居高不下。因此仍需探寻新的有效靶点，来预防和延缓骨质疏松症的发生和进展。我们前期研究数据显示，骨质疏松患者骨骼中Irg1的表达明显低于正常患者。Irg1在体内能催化合成细胞代谢产物衣康酸。我们发现Irg1敲除小鼠（Irg1-/-）表现出骨质疏松的表型，在其腹腔中注射外源性衣康酸后能延缓骨质疏松症的进展。通过RNA-seq分析和ShRNA沉默实验，我们发现衣康酸可通过G蛋白偶联受体Gpr161抑制破骨细胞分化。由此我们推测：Irg1可通过调控衣康酸的合成，进而促进衣康酸与Gpr161的结合，通过抑制破骨细胞分化在骨质疏松症中起到防治作用。本项目首次将细胞代谢产物衣康酸与骨质疏松症相关联，拟进一步通过构建小鼠骨质疏松模型，验证Irg1在骨质疏松症中的保护作用，为阐明骨质疏松症的发病机理及治疗骨质疏松症提供理论依据。

随着老龄化的不断加重，骨质疏松症的发病率伴随着提高，尽管目前有多种药物治疗骨质疏松症，但是药物的副作用多样，治疗效果也是层次不齐。骨质疏松性骨折对患者的生活质量以及经济水平产生了严重的影响。因此，仍需探寻新的有效靶点，来预防和延缓骨质疏松症的发生和进展。.本项目从人体自身代谢产物衣康酸着手，深入探讨了衣康酸在缓解骨质疏松症患者骨量丢失中的重要保护作用。阐明了衣康酸上游Irg1基因在骨质疏松中的效应，同时揭示了衣康酸通过调控破骨细胞分化在骨质疏松症中的重要机理。衣康酸作为内源性代谢产物，被证实在抗氧化应激、抗炎方面的重要作用，同时对人体的毒副作用基本忽略不计，为其远期临床应用创造了巨大的潜能。我们发现在病理状态下，Irg1基因能够通过促进衣康酸的表达，抑制巨噬细胞的炎症反应，同时抑制破骨细胞的分化与功能；Irg1基因敲除小鼠表现出明显的年龄相关的骨质疏松表型，进一步证实Irg1在骨质疏松疾病进展中的重要作用；在对Irg1敲除小鼠的高通量测序中，我们发现去磷酸酶DUSP6在破骨细胞分化过程中发挥着重要的作用，为后续进一步研究骨质疏松症的发病机理奠定了基础。.小分子化合物一直都是研究的热点，而人体的小分子代谢产物更是有着独特的先天性优势。多种外源性衣康酸的研发与制造，为后续衣康酸治疗骨质疏松症提供了强有力的保障。阐述衣康酸防治骨质疏松症的机理，明确其有效价值，对治疗与预防骨质疏松性骨折具有重要的现实意义。