Department of Biomedical Engineering, University of North Texas , Denton, Texas 76207, United States.
Department of Material Science and Engineering, University of North Texas , Denton, Texas 76207, United States.
ACS Appl Mater Interfaces. 2017 Aug 23;9(33):27453-27461. doi: 10.1021/acsami.7b06654. Epub 2017 Aug 8.
Zn biomaterials attract strong attentions recently for load-bearing medical implants because of their mechanical properties similar to bone, biocompatibility, and degradability at a more matched rate to tissue healing. It has been shown previously that Zn alloys are beneficial for bone regeneration, but the supporting mechanisms have not been explored in detail. Here, we studied the biological responses of human bone marrow mesenchymal stem cells (hMSC) to Zn and the underlying cellular signaling mechanisms. Typical Mg material AZ31 was used as a comparative benchmark control. Direct culture of cells on the materials revealed that cell adhesion, proliferation, and motility were higher on Zn than on AZ31. Significant cytoskeletal reorganizations induced by Zn or AZ31 were also observed. Mineralization of extracellular matrix (ECM) and hMSC osteogenic differentiation, measured by Alizarin red and ALP staining and activities, were significantly enhanced when cells were cultured with Zn or AZ31. Quantitative PCR also showed the increased expression of bone-related genes including ALP, collagen I, and osteopontin. Using small RNA interference to knockdown related key molecules, we illustrated the mechanisms of Zn-induced cellular signaling. TRPM7 and GPR39 appear to be the major cellular receptors facilitating Zn-entry into hMSC. The intracellular Zn then activates the cAMP-PKA pathway and triggers intracellular Ca responses, leading to activation of MAPK. In addition, Zn activates the Gαq-PLC-AKT pathway as well. Eventually, all of this signaling would lead to enhanced differential regulation of genes, cell survival/growth and differentiation, ECM mineralization, osteogenesis, and other cellular activities.
锌生物材料因其机械性能类似于骨骼、生物相容性和可降解性与组织愈合更匹配而受到关注，是一种用于承重医疗植入物的理想材料。以前已经表明，锌合金有利于骨再生，但支持机制尚未详细探索。在这里，我们研究了人骨髓间充质干细胞（hMSC）对锌的生物学反应及其潜在的细胞信号机制。典型的 Mg 材料 AZ31 被用作比较基准对照。细胞直接在材料上培养表明，细胞黏附、增殖和迁移在锌上比在 AZ31 上更高。还观察到由锌或 AZ31 诱导的细胞骨架的显著重排。通过茜素红和 ALP 染色和活性测量，细胞培养在锌或 AZ31 上时，细胞外基质（ECM）的矿化和 hMSC 成骨分化显著增强。定量 PCR 还显示包括碱性磷酸酶（ALP）、胶原蛋白 I 和骨桥蛋白在内的骨相关基因的表达增加。使用小 RNA 干扰敲低相关关键分子，我们说明了锌诱导的细胞信号转导的机制。TRPM7 和 GPR39 似乎是促进 hMSC 中锌进入的主要细胞受体。然后，细胞内的锌激活 cAMP-PKA 途径并触发细胞内 Ca 反应，导致 MAPK 的激活。此外，锌还激活 Gαq-PLC-AKT 途径。最终，所有这些信号转导都会导致基因的差异调控、细胞存活/生长和分化、ECM 矿化、成骨等细胞活动的增强。
