High Molecular Weight Poly(glutamic acid) to Improve BMP2-Induced Osteogenic Differentiation.
High Molecular Weight Poly(glutamic acid) to Improve BMP2-Induced Osteogenic Differentiation.
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DOI：
10.1021/acs.molpharmaceut.2c00141
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发表时间：
2022-12-05
影响因子：
4.9
通讯作者：
Sun, Hongli
中科院分区：
文献类型：
--
作者：
Hu, Jue;Wang, Zhuozhi;Miszuk, Jacob M.;Zeng, Erliang;Sun, Hongli
关键词：
fda批准的骨形态发生蛋白2 （BMP2）由于超高剂量要求而具有严重的副作用。肝素是研究最充分的硫酸化聚合物之一，用于稳定BMP2并改善其功能。然而，临床使用肝素是值得怀疑的，因为它的抗凝血活性不理想。最近的研究表明，聚谷氨酸（pGlu）有可能提高BMP2的生物活性，而安全性问题较少，然而关于pGlu的贡献仍然知之甚少。因此，我们旨在研究pGlu在bmp - 2诱导成骨中的作用及其在骨组织工程中的潜在应用。我们的数据首次表明，低分子量（L-pGlu）和高分子量（H-pGlu）均能显著改善MC3T3-E1前成骨细胞中bmp - 2诱导的早期成骨细胞分化标志物（ALP）。重要的是，与L-pGlu相比，H-pGlu能更快地增强基质矿化。此外，我们的数据表明，只有α-H-pGlu （α-H-pGlu）能显著提高BMP2的活性，而γ-H-pGlu （γ-H-pGlu）不能。此外，基因表达和矿化数据均表明，α-H-pGlu可使单剂量BMP2诱导高水平成骨细胞分化，而无需多剂量BMP2。为了研究pGlu在组织工程中的潜在应用，我们将H-pGlu+BMP2纳米复合物加入到胶原水凝胶中，显著提高了成骨细胞分化。此外，h -葡聚糖包被的3D多孔明胶和壳聚糖支架通过促进BMP2的持续释放显著增强成骨分化。因此，我们的研究结果表明，H-pGlu是一种有前景的新替代品，具有很大的骨组织工程应用潜力。
FDA-approved bone morphogenetic protein 2 (BMP2) has serious side effects due to the super high dose requirement. Heparin is one of the most well-studied sulfated polymers to stabilize BMP2 and improve its functionality. However, the clinical use of heparin is questionable because of its undesired anticoagulant activity. Recent study suggests that poly (glutamic acid) (pGlu) has the potential to improve BMP2 bioactivity with less safety concerns, however the knowledge on pGlu’s contribution remains largely unknown. Therefore, we aimed to study the role of pGlu in BMP2-induced osteogenesis and its potential application in bone tissue engineering. Our data, for the first time, indicated that both low (L-pGlu) and high molecular weight pGlu (H-pGlu) were able to significantly improve BMP2-induced early osteoblastic differentiation marker (ALP) in MC3T3-E1 pre-osteoblasts. Importantly, the matrix mineralization was more rapidly enhanced by H-pGlu compared to L-pGlu. Additionally, our data indicated that only alpha H-pGlu (α-H-pGlu) could significantly improve BMP2’s activity while gamma H-pGlu (γ-H-pGlu) failed to do so. Moreover, both gene expression and mineralization data demonstrated that α-H-pGlu enabled single-dose of BMP2 inducing high level of osteoblastic differentiation without multiple-dose of BMP2. To study the potential application of pGlu in tissue engineering, we incorporated the H-pGlu+BMP2 nanocomplexes into the collagen hydrogel with significantly elevated osteoblastic differentiation. Furthermore, H-pGlu-coated 3D porous gelatin and chitosan scaffolds significantly enhanced osteogenic differentiation through enabling sustained release of BMP2. Thus, our findings suggest H-pGlu is a promising new alternative with great potential for bone tissue engineering applications.
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