Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling
Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling
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衣康酸辛酯通过抑制 Hrd1 和激活 Nrf2 信号传导来抑制破骨细胞生成。
DOI：
10.1096/fj.201900887rr
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发表时间：
2019-11-01
期刊：
影响因子：
4.8
通讯作者：
Shi, Peihua
中科院分区：
文献类型：
--
作者：
Sun, Xuewu;Zhang, Boya;Shi, Peihua
内源性代谢物衣康酸已成为巨噬细胞功能的调节剂，可以限制炎症。然而，其对细胞分化和破骨细胞相关疾病的影响尚不清楚。本研究首次探讨衣康酸及其细胞渗透性衣康酸衍生物4-辛酯衣康酸（OI）在体外和体内对破骨细胞分化的影响。首先，我们证明衣康酸浓度在雌激素缺乏的小鼠中较低。成骨不全释放itaconate，诱导骨髓源性巨噬细胞在破骨细胞形成过程中表达核因子-红细胞2相关因子2 （Nrf2）。此外，经抗酒石酸酸性磷酸酶染色证实，OI显著抑制nf - κ B配体受体激活剂诱导的体外破骨细胞发生的早、中、晚期。此外，它还能显著抑制纤维肌动蛋白环的形成和体外骨吸收。在机制上，我们观察到OI通过抑制E3泛素连接酶（Hrd1）来抑制Nrf2与泛素的关联，从而增强了Nrf2的表达。OI还通过Hrd1抑制lps诱导的活性氧和炎症反应。建立了雌激素缺乏（通过卵巢切除术）引起的骨质疏松症模型。显微计算机断层扫描和组织学分析显示，成骨不全有效地抑制了卵巢切除术引起的骨质流失。综上所述，衣康酸衍生物OI在体外和体内均能抑制破骨细胞的发生，表明OI可能是治疗破骨细胞相关疾病的潜在药物；我们的研究结果也将它与骨质疏松症的发展联系起来。
The endogenous metabolite itaconate has emerged as a regulator of macrophage function that limits inflammation. However, its effect on cell differentiation and osteoclast-related diseases is unclear. Here, for the first time, we explored the effect of itaconate and its cell-permeable itaconate derivative, 4-octyl itaconate (OI) on osteoclast differentiation in vitro and in vivo. Firstly, we demonstrated that itaconate concentration was lower in estrogen-deficient mice. OI released itaconate and induced the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) in bone marrow-derived macrophages during osteoclastogenesis. Furthermore, OI significantly suppressed the early, middle, and late stages of osteoclastogenesis induced by receptor activator of NF-kappa B ligand in vitro, as confirmed by tartrate-resistant acid phosphatase staining. Moreover, it significantly inhibited fibrous actin ring formation and bone resorption in vitro. Mechanistically, we observed that OI enhanced Nrf2 expression by suppressing its association with ubiquitin via inhibition of the E3 ubiquitin ligase (Hrd1). OI also inhibited LPS-induced the reactive oxygen species and inflammatory responses via Hrd1. An estrogen deficiency (via ovariectomy)-induced osteoporosis model was also established. Here, on micro-computed tomography and histologic analysis showed that OI effectively suppressed ovariectomy-induced bone loss. In summary, OI, an itaconate derivative, can inhibit osteoclastogenesis in vitro and in vivo, indicating that OI could be a potential drug to treat osteoclast-related diseases; our results also link itaconate to the development of osteoporosis.