Amlexanox Enforces Osteogenic Differentiation and Bone Homeostasis Through Inhibiting Ubiquitin-Dependent Degradation of β-Catenin.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.101507
Qian He, Zhouboran Liu, Xuan Xia, Jun Zeng, Yuling Liu, Jingqiong Xun, Meilu Liu, Yueming Mei, Ruchun Dai
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Abstract

There was arising osteoporosis from an imbalance in bone remodeling, with excessive differentiation of bone marrow mesenchymal stem cells (BMSCs) into adipocytes instead of osteoblasts. In this study, we found IKKε was upregulated in osteoporotic bone and Ikbke knockdown promoted osteoblast differentiation. We explored amlexanox (AM), a novel IKKε inhibitor, for its effects on osteogenic differentiation and bone homeostasis. AM treatment in mice decreased bone loss, reduced marrow fat, and improved bone microarchitecture, leading to enhanced bone strength. In vitro, AM promoted osteogenesis and suppressed adipogenesis of BMSCs in a dose-dependent manner. Moreover, AM controlled RANKL/OPG expression of BMSC which regulated osteoclast differentiation. Mechanistic explorations revealed AM reinforced Wnt/β-catenin pathway by suppressing ubiquitin-proteasome-dependent degradation of β-catenin. Importantly, AM stimulated osteogenesis in human BMSCs. By promoting osteogenesis at the expense of adipogenesis and hindering osteoclastogenesis, AM offers a promising therapeutic strategy for osteoporosis due to its established safety profile.

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Amlexanox通过抑制β-Catenin的泛素依赖性降解促进成骨分化和骨稳态
由于骨髓间充质干细胞(BMSCs)过度分化为脂肪细胞而非成骨细胞,导致骨重塑失衡,从而引发骨质疏松症。本研究发现,IKKε在骨质疏松症骨中上调,Ikbke敲除可促进成骨细胞分化。我们探索了一种新型 IKKε 抑制剂--氨来呫诺(AM)对成骨分化和骨稳态的影响。AM治疗小鼠可减少骨质流失、减少骨髓脂肪、改善骨的微结构,从而增强骨强度。在体外,AM 能以剂量依赖的方式促进 BMSCs 的成骨和抑制脂肪生成。此外,AM 还能控制 BMSC 的 RANKL/OPG 表达,从而调节破骨细胞的分化。机理研究发现,AM通过抑制泛素蛋白酶体依赖的β-catenin降解,强化了Wnt/β-catenin通路。重要的是,AM能刺激人类BMSCs的成骨。AM以脂肪生成为代价促进骨生成,并阻碍破骨细胞生成,其安全性已得到证实,为骨质疏松症提供了一种有前景的治疗策略。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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