Fan Jiabing, Park Hyejin, Tan Steven, Lee Min
Division of Advanced Prosthodontics, University of California Los Angeles, Los Angeles, California, United States of America.
PLoS One. 2013 Aug 15;8(8):e72474. doi: 10.1371/journal.pone.0072474. eCollection 2013.
Bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors. However, BMPs are highly pleiotropic molecules and their supra-physiological high dose requirement leads to adverse side effects and inefficient bone formation. Thus, there is a need to develop alternative osteoinductive growth factor strategies that can effectively complement BMP activity. In this study, we intrinsically stimulated BMP signaling in adipose derived stem cells (ASCs) by downregulating noggin, a potent BMP antagonist, using an RNAi strategy. ASCs transduced with noggin shRNA significantly enhanced osteogenic differentiation of cells. The potency of endogenous BMPs was subsequently enhanced by stimulating ASCs with exogenous BMPs at a significantly reduced dose. The level of mineralization in noggin shRNA treated ASCs when treated with BMP-2 was comparable to that of control shRNA treated cell treated with 10-fold more BMP-2. The complementary strategy of noggin suppression + BMP-2 to enhance osteogenesis was further confirmed in 3D in vitro environments using scaffolds consisting of chitosan (CH), chondroitin sulfate (CS), and apatite layer on their surfaces designed to slowly release BMP-2. This finding supports the novel therapeutic potential of this complementary strategy in bone regeneration.
骨形态发生蛋白（BMPs）被认为是最有效的骨诱导因子。然而，BMPs是高度多效性的分子，其超生理高剂量需求会导致不良副作用和低效的骨形成。因此，需要开发能够有效补充BMP活性的替代性骨诱导生长因子策略。在本研究中，我们使用RNAi策略下调强效BMP拮抗剂头蛋白（noggin），从而内在地刺激脂肪来源干细胞（ASC）中的BMP信号传导。用noggin shRNA转导的ASC显著增强了细胞的成骨分化。随后，通过用显著降低剂量的外源性BMP刺激ASC，增强了内源性BMP的效力。用BMP-2处理时，noggin shRNA处理的ASC中的矿化水平与用10倍剂量BMP-2处理的对照shRNA处理细胞的矿化水平相当。在使用由壳聚糖（CH）、硫酸软骨素（CS）和表面设计用于缓慢释放BMP-2的磷灰石层组成的支架的3D体外环境中，进一步证实了noggin抑制+BMP-2增强成骨的互补策略。这一发现支持了这种互补策略在骨再生中的新治疗潜力。
