ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Johann Joachim Becher Weg 13, 55099 Mainz, Germany.
Int J Mol Sci. 2018 Jan 31;19(2):427. doi: 10.3390/ijms19020427.
Using femur explants from mice as an in vitro model, we investigated the effect of the physiological polymer, inorganic polyphosphate (polyP), on differentiation of the cells of the bone marrow in their natural microenvironment into the osteogenic and chondrogenic lineages. In the form of amorphous Ca-polyP nano/microparticles, polyP retains its function to act as both an intra- and extracellular metabolic fuel and a stimulus eliciting morphogenetic signals. The method for synthesis of the nano/microparticles with the polyanionic polyP also allowed the fabrication of hybrid particles with the bisphosphonate zoledronic acid, a drug used in therapy of bone metastases in cancer patients. The results revealed that the amorphous Ca-polyP particles promote the growth/viability of mesenchymal stem cells, as well as the osteogenic and chondrogenic differentiation of the bone marrow cells in rat femur explants, as revealed by an upregulation of the expression of the transcription factors (differentiation towards osteoblasts) and (chondrocyte differentiation). In parallel to this bone anabolic effect, incubation of the femur explants with these particles significantly reduced the expression of the gene encoding the osteoclast bone-catabolic enzyme, cathepsin-K, while the expression of the tartrate-resistant acid phosphatase remained unaffected. The gene expression data were supported by the finding of an increased mineralization of the cells in the femur explants in response to the Ca-polyP particles. Finally, we show that the hybrid particles of polyP complexed with zoledronic acid exhibit both the cytotoxic effect of the bisphosphonate and the morphogenetic and mineralization inducing activity of polyP. Our results suggest that the Ca-polyP nano/microparticles are not only a promising scaffold material for repairing long bone osteo-articular damages but can also be applied, as a hybrid with zoledronic acid, as a drug delivery system for treatment of bone metastases. The polyP particles are highlighted as genuine, smart, bioinspired nano/micro biomaterials.
使用来自小鼠的股骨外植体作为体外模型，我们研究了生理聚合物无机多聚磷酸盐（polyP）对骨髓细胞在其自然微环境中向成骨和软骨谱系分化的影响。多聚磷酸盐以无定形 Ca-polyP 纳米/微米颗粒的形式存在，保留了作为细胞内和细胞外代谢燃料以及引发形态发生信号的刺激物的功能。合成带负电荷的多聚磷酸盐纳米/微米颗粒的方法还允许与双膦酸盐唑来膦酸（一种用于治疗癌症患者骨转移的药物）制造杂化颗粒。结果表明，无定形 Ca-polyP 颗粒促进了间充质干细胞的生长/活力，以及大鼠股骨外植体骨髓细胞的成骨和软骨分化，这表现为转录因子的表达上调（向成骨细胞分化）和 （软骨细胞分化）。与这种骨合成作用平行的是，用这些颗粒孵育股骨外植体显著降低了编码破骨细胞骨分解酶组织蛋白酶-K 的基因的表达，而抗酒石酸酸性磷酸酶的表达不受影响。基因表达数据得到了股骨外植体中细胞矿化增加的支持，这是对 Ca-polyP 颗粒的反应。最后，我们表明与唑来膦酸复合的 polyP 杂化颗粒既表现出双膦酸盐的细胞毒性作用，又表现出 polyP 的形态发生和矿化诱导活性。我们的结果表明，Ca-polyP 纳米/微米颗粒不仅是修复长骨骨关节损伤的有前途的支架材料，而且还可以作为与唑来膦酸的杂化物用作治疗骨转移的药物输送系统。多聚磷酸盐颗粒被强调为真正的、智能的、仿生纳米/微生物材料。
