ACT001通过抑制NF-κB/NLRP3信号通路改善ovx诱导的骨质疏松症。

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yuan Li, Jin-Yu Yang, Ma-Li Lin, Tian-Zhu Liu, Wen-Na Lu, Ying Yang, Zhong-Cheng Liu, Jian-Heng Li, Guo-Qiang Zhang, Jian-Shuang Guo
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引用次数: 0

摘要

骨质疏松症(Osteoporosis, OP)是一种常见的全身性代谢性骨病,以骨量减少和破骨细胞过度活跃为特征。ACT001已被FDA批准为孤儿药,并显示出对组织损伤的多重保护作用。然而,其在预防破骨细胞分化中的作用及其潜在机制尚未阐明。本研究表明,ACT001通过抑制Nfatc1、TRAP、Ctsk、Dc-stamp的表达抑制rankl诱导的破骨细胞分化和F-actin环的形成,体外无明显细胞毒性。ACT001抑制NF-κB的磷酸化和NLRP3炎性体的激活,从而降低焦热相关蛋白的表达。(GSDMD, caspase-1, IL-1β, IL-18)。与ACT001一致,NLRP3炎性体抑制剂MCC950治疗也通过抑制Nfatc1的转录激活来抑制破骨细胞的发生。此外,ACT001可以保护卵巢切除引起的小鼠骨丢失,减少破骨细胞的数量,下调NLRP3和IL-1β的表达。这些数据表明,ACT001可以通过抑制NF-κB/NLRP3通路,减少rankl诱导的破骨细胞分化,减轻雌激素缺乏导致的骨质流失,提示其在维持骨稳态和治疗骨质疏松症方面的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ACT001 improves OVX-induced osteoporosis by suppressing the NF-κB/NLRP3 signaling pathway.

Osteoporosis (OP) is a common systemic metabolic bone disease characterized by the decrease in bone mass and hyperactivity of osteoclasts. ACT001 is approved as an orphan drug by FDA and has shown multiple protective effects against tissue injury. However, its role in prevention of osteoclast differentiation and the underlying mechanisms have not been elucidated. Herein, we show that ACT001 inhibited RANKL-induced osteoclast differentiation and F-actin ring formation through suppressing the expression of Nfatc1, TRAP, Ctsk, Dc-stamp without obvious cytotoxicity in vitro. ACT001 restrained the phosphorylation of NF-κB and the activation of NLRP3 inflammasome, thereby decreased the expression of pyroptosis-related protein. (GSDMD, caspase-1, IL-1β, IL-18). Consistent with ACT001, the NLRP3 inflammasome inhibitor MCC950 treatment also suppressed the osteoclastogenesis through inhibiting the transcriptional activation of Nfatc1. Furthermore, ACT001 protected ovariectomy-induced bone loss in mice, reduced the number of osteoclasts, downregulated the expression of NLRP3 and IL-1β. These data indicate that ACT001 can reduce RANKL-induced osteoclast differentiation through suppressing the NF-κB/NLRP3 pathway, and attenuate the bone loss induced by estrogen-deficiency, suggesting its therapeutic potential for bone homeostasis maintenance and osteoporosis treatment.

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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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