One-day treatment of small molecule 8-bromo-cyclic AMP analogue induces cell-based VEGF production for in vitro angiogenesis and osteoblastic differentiation.
One-day treatment of small molecule 8-bromo-cyclic AMP analogue induces cell-based VEGF production for in vitro angiogenesis and osteoblastic differentiation.
复制标题
DOI：
10.1002/term.1839
复制
发表时间：
2016-10
影响因子：
3.3
通讯作者：
Laurencin, Cato T.
中科院分区：
文献类型：
--
作者：
Lo, Kevin W. -H.;Kan, Ho Man;Gagnon, Keith A.;Laurencin, Cato T.
关键词：
基于小分子的再生工程正在成为一种有前途的骨组织再生策略。小分子cAMP类似物已被提出作为用于骨修复和再生的新型生物因子，并且虽然有希望，但这些小分子对血管生成（成功骨再生的关键要求）的影响仍不清楚。我们以前的研究表明，小分子cAMP类似物8-溴腺苷-3 '，5'-环一磷酸（8-Br-cAMP）能够通过cAMP信号级联促进成骨细胞在聚合物支架上的初始粘附。在这里，我们报告说，8-Br-cAMP是能够诱导在体外细胞为基础的血管生成促进VEGF的生产。我们首先证明，用8-Br-cAMP处理成骨样MC 3 T3-E1细胞一天显著增加VEGF的产生和分泌。然后，我们证明，8-Br-cAMP诱导的细胞分泌的VEGF是生物活性的，并可能促进血管生成，增加内皮细胞（HUVECs）迁移和小管形成证明。此外，用8-Br-cAMP处理MC 3 T3-E1细胞短至一天导致ALP活性增强以及基质矿化，证明了体外成骨细胞分化。短期8-Br-cAMP处理也解决了非特异性细胞毒性的问题，因为我们的数据表明，一天的8-Br-cAMP处理方案支持MC 3 T3-E1细胞以及HUVEC的细胞增殖。虽然与小分子药物相关的主要问题是非特异性细胞毒性的风险，但本文中概述的短期暴露治疗提供了一种非常有前途的策略来减轻与小分子相关的风险。
Small molecule based regenerative engineering is emerging as a promising strategy for regenerating bone tissue. Small molecule cAMP analogues have been proposed as novel biofactors for bone repair and regeneration, and while promising, the effect that these small molecules have on angiogenesis, a critical requirement for successful bone regeneration, is still unclear. Our previous research demonstrated that the small molecule cAMP analogue 8-bromoadenosine-3’,5’-cyclic monophosphate (8-Br-cAMP) was able to promote initial osteoblast adhesion on a polymeric scaffold via cAMP signaling cascades. Here, we report that 8-Br-cAMP is capable of inducing in vitro cell-based VEGF production for angiogenesis promotion. We first demonstrated that treating osteoblast-like MC3T3-E1 cells with 8-Br-cAMP for one day significantly increased VEGF production and secretion. We then demonstrated that 8-Br-cAMP induced cell-secreted VEGF is biologically active and may promote angiogenesis as evidenced by increased endothelial cells (HUVECs) migration and tubule formation. In addition, treatment of MC3T3-E1 cells with 8-Br-cAMP for as short as a single day resulted in enhanced ALP activity as well as matrix mineralization, demonstrating in vitro osteoblastic differentiation. A short term 8-Br-cAMP treatment also addresses the concern of non-specific cytotoxicity, as our data indicate that a one-day 8-Br-cAMP treatment scheme supports cellular proliferation of MC3T3-E1 cells as well as HUVECs. While the major concern associated with small molecule drugs is the risk of non-specific cytotoxicity, the short exposure treatment outlined in this paper provides a very promising strategy to mitigate the risk associated with small molecules.
登录
查看更多内容
影响因子：
4.1
作者：
Doorn, Joyce;Leusink, Maarten;de Boer, Jan
通讯作者：
de Boer, Jan
影响因子：
14
作者：
Doorn, Joyce;Fernandes, Hugo A. M.;de Boer, Jan
通讯作者：
de Boer, Jan
影响因子：
4.8
作者：
Christensen, AE;Selheim, F;Doskeland, SO
通讯作者：
Doskeland, SO
影响因子：
3.3
作者：
Kim, Jinku;Sharma, Aditi;Runge, Brett;Waters, Heather;Doll, Bruce;McBride, Sean;Alvarez, Pedro;Dadsetan, Mahrokh;Yaszemski, Michael J.;Hollinger, Jeffrey O.
通讯作者：
Hollinger, Jeffrey O.
影响因子：
3.3
作者：
Lo, Kevin W. -H.;Kan, Ho Man;Ashe, Keshia M.;Laurencin, Cato T.
通讯作者：
Laurencin, Cato T.