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Abstract
Osteoporosis results from the imbalance between bone resorption and bone formation, and restoring the normal balance of bone remodeling is highly desirable for identification of better treatment. In this study, using a cell-based high-throughput screening model representing Runt-related transcription factor 2 (RUNX2) transcriptional activity, we identified a novel small-molecular-weight compound, T63, as an efficient up-regulator of osteogenesis. T63 increased the alkaline phosphatase (ALPL) activity and mineralization as well as gene expression of Alpl and other osteogenic marker genes in mouse osteoblasts and mesenchymal stem cell-like cells. Upon induction of osteoblast differentiation, T63 inhibited adipogenic differentiation in the pluripotent mesenchymal cells. Consistently, T63 up-regulated RUNX2 mRNA and protein levels, and knockdown of RUNX2 reduced the osteogenic role of T63. Mechanistically, T63 activated both BMPs and WNT/β-catenin signaling pathways. Inhibition of either signaling pathway with specific inhibitor suppressed T63-induced RUNX2 expression and the osteogenic phenotypes. Moreover, T63 markedly protected against bone mass loss in the ovariectomized and dexamethasone treated rat osteoporosis model. Collectively, our data demonstrate that T63 could be a promising drug candidate and deserves further development for potential therapeutics in osteoporosis.
Highlights
Osteoporosis is caused by the imbalance between osteoclastic bone resorption and osteoblastic bone formation, and has become one of the major global health concerns during aging development[1]
RUNX2 binds to a conserved nucleotide sequence (R/TACCRCA), which is named as the osteoblast specific element 2 (OSE2) in osteoblasts, and regulates the transcription of numerous genes, including alkaline phosphatase (Alpl), bone matrix protein encoding genes secreted phosphoprotein 1 (Spp[1], named as osteopontin) and bone gamma-carboxyglutamate protein (Bglap, named as osteocalcin)[6, 7], all of which act to induce osteoblastic mineralization[7, 8]
RUNX2 is considered as a pivotal mediator of a variety of signal pathways, including bone morphogenetic proteins (BMPs) and WNT/β-catenin signaling pathways, which are involved in the regulation of osteoblast differentiation[9,10,11,12,13]
Summary
Osteoporosis is caused by the imbalance between osteoclastic bone resorption and osteoblastic bone formation, and has become one of the major global health concerns during aging development[1]. RUNX2 is considered as a pivotal mediator of a variety of signal pathways, including bone morphogenetic proteins (BMPs) and WNT/β-catenin signaling pathways, which are involved in the regulation of osteoblast differentiation[9,10,11,12,13]. Several compounds such as epicatechin gallate, fisetin www.nature.com/scientificreports/. Mechanistic study revealed that T63 potentiated the osteogenic differentiation through activating both BMPs and WNT/β-catenin signaling pathways, leading to the increased RUNX2 expression and its osteogenic activity
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