Acceleration of osteoblast differentiation by a novel osteogenic compound, DMP-PYT, through activation of both the BMP and Wnt pathways

Abstract

Osteoblast differentiation is regulated through the successive activation of signaling molecules by a complex interplay of extracellular signals such as bone morphogenetic protein (BMP) and Wnt ligands. Numerous studies have identified natural as well as synthetic compounds with osteogenic activity through the regulation of either BMP/SMADs or the Wnt/β-catenin pathway. Here, we attempted to isolate small molecules that concurrently activated both SMADs and β-catenin, which led to the discovery of a novel potent osteogenic compound, DMP-PYT. Upon BMP2 stimulation, DMP-PYT substantially increased osteoblast differentiation featured by enhanced expression of osteoblast-specific genes and accelerated calcification through activation of BMPs expression. DMP-PYT promoted BMP2-induced SMAD1/5/8 phosphorylation and β-catenin expression, the latter in a BMP2-independent manner. DMP-PYT alone enhanced nuclear localization of β-catenin to promote the DNA-binding and transcriptional activity of T-cell factor, thereby resulting in increased osteoblast differentiation in the absence of BMP2. Most importantly, DMP-PYT advanced skeletal development and bone calcification in zebrafish larvae. Conclusively, DMP-PYT strongly stimulated osteoblast differentiation and bone formation in vitro and in vivo by potentiating BMP2-induced activation of SMADs and β-catenin. These results suggest that DMP-PYT may have beneficial effects for preventing and for treating osteoporosis.

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“…62e64 On BMP2 stimulation, calcification and skeletal development processes could be accelerated through activation of BMP and Wnt pathways. 65 Moreover, BMP2 deficiency could block the ability of the WNT signaling pathway to promote osteogenesis. 66 Thus, although it is still necessary to investigate mechanistic links of ENST00000607393 expression and glaucoma, it is possible that ENST00000607393 knockdown might exert its action through the Wnt signaling pathway.…”

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“…Small molecules were isolated that activated both SMADs and β-catenin, that led to the discovery of a novel potent osteogenic compound, DMP-PYT. They worked through BMP2 stimulation, DMP-PYT substantially increased osteoblast differentiation through enhanced expression of osteoblast-specific genes and accelerated calcification featured by activation of BMPs expression [22]. DMP-PYT promoted BMP2induced SMAD1/5/8 phosphorylation and β-catenin expression, the latter in a BMP2-independent manner.…”

“…DMP-PYT promoted BMP2induced SMAD1/5/8 phosphorylation and β-catenin expression, the latter in a BMP2-independent manner. DMP-PYT alone enhanced nuclear localization of β-catenin to promote the DNA-binding and transcriptional activity of T-cell factor, thereby resulting in increased osteoblast differentiation in the absence of BMP2 [22].…”

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