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

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

  • Int J Biol Sci. 2024 Sep 30;20(13):5254-5271. doi: 10.7150/ijbs.101507.
Qian He 1,  Zhouboran Liu 1,  Xuan Xia 2 3,  Jun Zeng 4,  Yuling Liu 1,  Jingqiong Xun 5,  Meilu Liu 1,  Yueming Mei 1,  Ruchun Dai 1
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Physiology and Pathophysiology, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, P.R. China.
  • 3 Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, P.R. China.
  • 4 Department of Endocrinology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital. Yichang 443002, P.R. China.
  • 5 Department of Endocrinology, Guizhou Provincial People's Hospital. Guiyang 550002, P.R. China.
PMID: 39430247 DOI: 10.7150/ijbs.101507
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.

Keywords

Amlexanox; BMSCs; IKKε; Osteoporosis.; Ubiquitination; β-catenin.

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