Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Korea.
College of Pharmacy and Bio-MAX Institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
J Cell Physiol. 2023 Sep;238(9):2063-2075. doi: 10.1002/jcp.31064. Epub 2023 Jun 19.
Cholesterol sulfate (CS) is an activator of retinoic acid-related orphan receptor α (RORα). CS treatment or RORα overexpression attenuates osteoclastogenesis in a collagen-induced arthritis mouse model. However, the mechanism by which CS and RORα regulate osteoclast differentiation remains largely unknown. Thus, we aimed to investigate the role of CS and RORα in osteoclastogenesis and their underlying mechanism. CS inhibited osteoclast differentiation, but RORα deficiency did not affect osteoclast differentiation and CS-mediated inhibition of osteoclastogenesis. CS enhanced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and sirtuin1 (Sirt1) activity, leading to nuclear factor-κB (NF-κB) inhibition by decreasing acetylation at Lys310 of p65. The NF-κB inhibition was restored by AMPK inhibitor, but the effects of CS on AMPK and NF-κB were not altered by RORα deficiency. CS also induced osteoclast apoptosis, which may be due to sustained AMPK activation and consequent NF-κB inhibition, and the effects of CS were significantly reversed by interleukin-1β treatment. Collectively, these results indicate that CS inhibits osteoclast differentiation and survival by suppressing NF-κB via the AMPK-Sirt1 axis in a RORα-independent manner. Furthermore, CS protects against bone destruction in lipopolysaccharide- and ovariectomy-mediated bone loss mouse models, suggesting that CS is a useful therapeutic candidate for treating inflammation-induced bone diseases and postmenopausal osteoporosis.
硫酸胆固醇 (CS) 是维甲酸相关孤儿受体 α (RORα) 的激活剂。CS 处理或 RORα 过表达可减轻胶原诱导性关节炎小鼠模型中的破骨细胞生成。然而，CS 和 RORα 调节破骨细胞分化的机制在很大程度上仍然未知。因此，我们旨在研究 CS 和 RORα 在破骨细胞生成中的作用及其潜在机制。CS 抑制破骨细胞分化，但 RORα 缺失不影响破骨细胞分化和 CS 介导的破骨细胞生成抑制。CS 增强 AMP 激活的蛋白激酶 (AMPK) 磷酸化和 Sirtuin1 (Sirt1) 活性，通过减少 p65 的 Lys310 乙酰化来抑制核因子-κB (NF-κB)。AMPK 抑制剂可恢复 NF-κB 的抑制，但 RORα 缺失并不改变 CS 对 AMPK 和 NF-κB 的作用。CS 还诱导破骨细胞凋亡，这可能是由于 AMPK 的持续激活和随后的 NF-κB 抑制，CS 的作用可被白细胞介素 1β 处理显著逆转。总之，这些结果表明，CS 通过 AMPK-Sirt1 轴抑制 NF-κB，在不依赖 RORα 的情况下抑制破骨细胞分化和存活。此外，CS 可预防脂多糖和卵巢切除术介导的骨丢失小鼠模型中的骨破坏，表明 CS 是治疗炎症性骨病和绝经后骨质疏松症的一种有用的治疗候选物。
