Abstract:
Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.
摘要:
通过小分子激活Nrf2是治疗绝经后骨质疏松症的有希望的策略。然而,目前尚无Nrf2激活剂被批准用于治疗慢性病,Nrf2调控破骨细胞分化的下游机制尚不清楚。这里,我们发现bitopertin,临床阶段甘氨酸摄取抑制剂,通过激活Nrf2抑制破骨细胞分化并改善卵巢切除术引起的骨丢失。机械上,bitopertin与Keap1Kelch结构域相互作用并降低Keap1-Nrf2结合,导致Nrf2泛素化和降解减少。Bitopertin在小鼠和人类受试者中与临床批准的Nrf2激活剂相比与较少的不良事件相关。此外,Nrf2转录激活铁转运蛋白编码基因Slc40a1以降低破骨细胞细胞内铁水平。Nrf2的缺失或铁补充上调鸟氨酸代谢酶Odc1,其降低鸟氨酸水平,从而促进破骨细胞分化。总的来说,我们的研究结果确定了一种新的临床阶段Nrf2激活剂,并在破骨细胞中提出了一种新的Nrf2-铁-鸟氨酸代谢轴.