National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, P.R. China.
Department of Physiology and Pathophysiology, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, P.R. China.
Int J Biol Sci. 2024 Sep 30;20(13):5254-5271. doi: 10.7150/ijbs.101507. eCollection 2024.
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 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.
存在由骨重建失衡引起的骨质疏松症，骨髓间充质干细胞（BMSCs）过度分化为脂肪细胞而不是成骨细胞。在这项研究中，我们发现 IKKε 在骨质疏松症骨中上调，并且敲低促进成骨细胞分化。我们探索了新型 IKKε 抑制剂 amlexanox（AM）对成骨分化和骨稳态的影响。在小鼠中，AM 治疗可减少骨丢失、减少骨髓脂肪并改善骨微结构，从而增强骨强度。体外，AM 以剂量依赖性方式促进 BMSCs 的成骨分化并抑制脂肪生成。此外，AM 控制了调节破骨细胞分化的 BMSC 的 RANKL/OPG 表达。机制探索表明，AM 通过抑制β-连环蛋白的泛素蛋白酶体依赖性降解来增强 Wnt/β-连环蛋白通路。重要的是，AM 刺激人 BMSCs 的成骨作用。通过促进成骨作用而不是脂肪生成并抑制破骨细胞生成，AM 提供了一种有前途的骨质疏松症治疗策略，因为其具有既定的安全性。
