硫酸化减轻25-羟基胆固醇对绝经后骨丢失的缓解作用
Sulfation Attenuates Mitigating Effects of 25-Hydroxycholesterol on Postmenopausal Bone Loss.
摘要(中文译文)
绝经后骨质疏松症是一种常见的骨骼疾病，目前仍缺乏更安全的治疗策略。虽然某些氧固醇具有成骨诱导潜力，但25-羟基胆固醇（25HC）在骨稳态中的作用仍不清楚。此外，25HC可发生硫酸化修饰——一种尚未被充分探索的化学修饰——形成25HC3S。本研究旨在探讨25HC和25HC3S对骨丢失的影响及其潜在机制。我们发现，在卵巢切除（OVX）小鼠骨质疏松模型中，25HC治疗而非25HC3S治疗可改善骨丢失，表现为骨量和I型胶原表达增加，同时破骨细胞数量减少。转录组分析显示，25HC在骨组织和成骨谱系细胞培养中调控与细胞周期和Rho GTP酶信号通路相关的基因，而25HC3S的作用减弱。体内和体外实验表明，25HC促进前成骨细胞增殖并增强骨细胞存活。在机制上，25HC在前成骨细胞中抑制Rho GTP酶信号通路，但在骨细胞中激活该通路，而硫酸化修饰在很大程度上消除了这一效应。总之，本研究将25HC确定为对抗绝经后骨丢失的保护性调节因子，并揭示硫酸化修饰是消除其有益作用的关键开关，支持补充25HC作为骨质疏松症的有前景的治疗策略。
Abstract
Postmenopausal osteoporosis is a prevalent skeletal disorder with an unmet need for safer therapeutic strategies. While certain oxysterols show osteoinductive potential, the role of 25-hydroxycholesterol (25HC) in bone homeostasis remains unclear. Furthermore, 25HC can undergo sulfation, a largely underexplored chemical modification, to form 25HC3S. This study aimed to investigate the effects of 25HC and 25HC3S on bone loss and the underlying mechanisms. We found that treatment with 25HC, but not 25HC3S, ameliorated bone loss in an ovariectomized (OVX) mouse model of osteoporosis, as evidenced by increased bone mass and expression of type I collagen, alongside decreased osteoclast numbers. Transcriptomic analysis revealed that 25HC regulated genes related to cell cycle and Rho GTPase signaling in bone tissue and osteoblastic lineage cell cultures, while 25HC3S had attenuated effects. In vivo and in vitro experiments demonstrated that 25HC promoted pre-osteoblast proliferation and enhanced osteocyte survival. Mechanistically, 25HC inhibited Rho GTPase signaling in pre-osteoblasts but activated it in osteocytes, which was largely abolished by sulfation. Collectively, this study identifies 25HC as a protective regulator against postmenopausal bone loss and unveils sulfation as a critical switch that negates its benefit, supporting 25HC supplementation as promising therapeutic strategies for osteoporosis.
如何引用
AMA
He Liu, Wenrui Ma, Yichen Niu, Xiaodan Ji, Liangjie Huang, Jingyan Hu, et al. Sulfation Attenuates Mitigating Effects of 25-Hydroxycholesterol on Postmenopausal Bone Loss.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2026; doi:10.1096/fj.202600557R.
APA
He Liu, Wenrui Ma, Yichen Niu, Xiaodan Ji, Liangjie Huang, Jingyan Hu, et al (2026). Sulfation Attenuates Mitigating Effects of 25-Hydroxycholesterol on Postmenopausal Bone Loss.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202600557R
GB/T 7714
He Liu, Wenrui Ma, Yichen Niu, Xiaodan Ji, Liangjie Huang, Jingyan Hu, et al. Sulfation Attenuates Mitigating Effects of 25-Hydroxycholesterol on Postmenopausal Bone Loss.[J]. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026 doi:10.1096/fj.202600557R.
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