A synthetic compound that potentiates bone morphogenetic protein-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype.
A synthetic compound that potentiates bone morphogenetic protein-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype.
复制标题
DOI：
10.1007/s11010-010-0664-6
复制
发表时间：
2011-03
影响因子：
4.3
通讯作者：
Boden, Scott D.
中科院分区：
文献类型：
--
作者：
Kato, Satoshi;Sangadala, Sreedhara;Tomita, Katsuro;Titus, Louisa;Boden, Scott D.
目前迫切需要开发一种方法来降低使用重组人骨形态发生蛋白(BMPs)促进骨诱导的成本。在这项研究中，我们证明了一种低分子化合物SVAK-12的成骨作用，它增强了BMP-2诱导C2C12成肌细胞转分化为成骨表型的作用。在这里，我们报告了一种特定的化合物，SVAK-12，它是基于小分子数据库的电子筛选，使用SMurf1-WW2结构域的同源建模相互作用基序来选择的。SVAK-12对BMP-2活性的增强是通过评估BMP特异性的报告活性和监测BMP-2诱导的骨钙素和碱性磷酸酶(ALP)的表达来表征的，骨钙素和碱性磷酸酶(ALP)是广泛接受的成骨细胞分化的标志基因。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，以成骨Smads为靶标，通过泛素介导的蛋白酶体降解。在S-1−/−基因敲除小鼠中，S-1是一个有趣的潜在的促进骨形成的靶点，基于阻断S-1结合到Smad靶点的蛋白质对骨骼的积极作用。由于Smads通过其WW2结构域与SMurf1结合，我们进行了电子筛选，以确定可能与SMurf1-WW2结构域相互作用的化合物。我们最近报道了一种化合物SVAK-3的活性。然而，SVAK-3虽然表现出增强BMP的活性，但并不稳定，因此需要在选定的候选化合物中重新寻找更稳定和有效的化合物。除了更稳定之外，SVAK-12在诱导成肌细胞C2C12细胞分化方面表现出剂量依赖的活性，即使在并行监测成骨细胞表型的多个标记时也是如此。
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.
登录
查看更多内容
影响因子：
3.5
作者：
BOHM, HJ
通讯作者：
BOHM, HJ
影响因子：
64.5
作者：
Yamashita, M;Ying, SX;Zhang, YE
通讯作者：
Zhang, YE
DOI：
10.1080/07391102.2007.10507151
发表时间：
2007-08-01
影响因子：
4.4
作者：
Sangadala, Sreedhara;Metpally, Raghu Prasad Rao;Reddy, Boojala Vijay B.
通讯作者：
Reddy, Boojala Vijay B.
影响因子：
3.5
作者：
BOHM, HJ
通讯作者：
BOHM, HJ
影响因子：
3
作者：
Boden, SD;Schimandle, JH;Hutton, WC
通讯作者：
Hutton, WC