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A synthetic compound that potentiates bone morphogenetic protein-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype

机译:一种合成化合物,可增强骨形态发生蛋白-2诱导的成肌细胞转分化为成骨细胞表型

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摘要

There is an urgent need to develop methods that lower costs of using recombinant human bone morphogenetic proteins (BMPs) to promote bone induction. In this study, we demonstrate the osteogenic effect of a low-molecular weight compound, SVAK-12, that potentiated the effects of BMP-2 in inducing transdifferentiation of C2C12 myoblasts into the osteoblastic phenotype. Here, we report a specific compound, SVAK-12, which was selected based on in silico screenings of small-molecule databases using the homology modeled interaction motif of Smurf1-WW2 domain. The enhancement of BMP-2 activity by SVAK-12 was characterized by evaluating a BMP-specific reporter activity and by monitoring the BMP-2-induced expression of mRNA for osteocalcin and alkaline phosphatase (ALP), which are widely accepted marker genes of osteoblast differentiation. Finally, we confirmed these results by also measuring the enhancement of BMP-2-induced activity of ALP. Smurf1 is an E3 ligase that targets osteogenic Smads for ubiquitin-mediated proteasomal degradation. Smurf1 is an interesting potential target to enhance bone formation based on the positive effects on bone of proteins that block Smurf1-binding to Smad targets or in Smurf1-/- knockout mice. Since Smads bind Smurf1 via its WW2 domain, we performed in silico screening to identify compounds that might interact with the Smurf1-WW2 domain. We recently reported the activity of a compound, SVAK-3. However, SVAK-3, while exhibiting BMP-potentiating activity, was not stable and thus warranted a new search for a more stable and efficacious compound among a selected group of candidates. In addition to being more stable, SVAK-12 exhibited a dose-dependent activity in inducing osteoblastic differentiation of myoblastic C2C12 cells even when multiple markers of the osteoblastic phenotype were parallelly monitored. © 2010 Springer Science+Business Media, LLC.
机译:迫切需要开发降低使用重组人骨形态发生蛋白(BMP)促进骨诱导的成本的方法。在这项研究中,我们证明了低分子量化合物SVAK-12的成骨作用,该作用增强了BMP-2诱导C2C12成肌细胞转分化为成骨细胞表型的作用。在这里,我们报告了一种特定的化合物SVAK-12,该化合物是根据使用Smurf1-WW2域的同源性建模相互作用基序对小分子数据库进行计算机筛选而选择的。通过评估BMP特异的报道分子活性并监测BMP-2诱导的骨钙素和碱性磷酸酶(ALP)的mRNA表达来表征SVAK-12增强BMP-2活性,这是成骨细胞的标记基因差异化。最后,我们还通过测量BMP-2诱导的ALP活性的增强来证实这些结果。 Smurf1是一种E3连接酶,其靶向成骨Smads引起遍在蛋白介导的蛋白酶体降解。 Smurf1是一种有趣的潜在靶标,它基于阻止Smurf1结合Smad靶标或Smurf1-/-基因敲除小鼠的蛋白质对骨骼的正作用而增强骨骼的形成。由于Smads通过其WW2域与Smurf1结合,我们进行了计算机筛选,以鉴定可能与Smurf1-WW2域相互作用的化合物。我们最近报道了化合物SVAK-3的活性。但是,SVAK-3表现出BMP增强活性,但不稳定,因此有必要在选定的候选组中重新寻找更稳定和有效的化合物。除了更稳定之外,即使同时监测成骨细胞表型的多个标记,SVAK-12在诱导成肌细胞C2C12细胞的成骨细胞分化中也表现出剂量依赖性的活性。 ©2010 Springer Science + Business Media,LLC。

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