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

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 IKKe was upregulated in osteoporotic bone and Ikbke knockdown promoted osteoblast differentiation. We explored amlexanox (AM), a novel IKKe 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/beta-catenin beta- catenin pathway by suppressing ubiquitin-proteasome-dependent degradation of beta-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.