Dual regulation of phaseol on osteoclast formation and osteoblast differentiation by targeting TAK1 kinase for osteoporosis treatment

作者：Lihua Tan, Zhimin Miao, Yuxin Zhao, Yongkai Liang, Nan Xu, Xin Chen, Yanbei Tu, Chengwei He · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.12.009 · 被引用次数：14 · 研究领域：Bone Metabolism and Diseases、Bone health and osteoporosis research、Phytoestrogen effects and research

INTRODUCTION: Osteoporosis is an osteolytic disorder resulting from an inequilibrium between osteoblast-mediated osteogenesis and osteoclast-driven bone absorption. Safe and effective approaches for osteoporosis management are still highly demanded. PURPOSE: This study aimed to examine the osteoprotective effect and the mechanisms of phaseol (PHA) in vitro and in vivo. METHODS: Virtual screening identified the potential inhibitors of transforming growth factor-beta-activated kinase 1 (TAK1) from coumestans. The interaction between PHA and TAK1 was investigated by molecular simulation, pronase and thermal resistance assays. The maturation and function of osteoclasts were determined using tartrate-resistant acid phosphatase staining, bone absorption and F-actin ring formation assays. The differentiation and calcification of osteoblasts were assessed by alkaline phosphatase staining and Alizarin Red S staining. The activity of related targets and pathways were detected using immunoblotting, immunofluorescence and co-immunoprecipitation assays. The in vivo osteoprotective effect of PHA was evaluated using a lipopolysaccharide (LPS)-induced mouse osteoporosis model. RESULTS: Firstly, we confirmed that TAK1 was essential in controlling bone remodeling by regulating osteogenesis and osteoclastogenesis. Moreover, PHA, a coumestan compound predominantly present in leguminous plants, was identified as a potent TAK1 inhibitor through virtual and real experiments. Subsequently, PHA was o...