锶对基质小泡介导的骨矿化的调控及作用机理研究

Recently, strontium (Sr) and related compounds have shown huge application potential in the treatment of osteoporosis and related fractures, because it can concomitantly induce bone formation and inhibit bone resorption. Most of the recent studies focused on observing the osteoblastic activities regulated by Sr during the early stage of bone mineralization, but little attention was paid on the deficient mineralization induced by Sr that deposited in bone matrix in the late stage. Matrix vesicles released by osteoblasts play an important role during bone matrix mineralization. They are enriched in various kinds of phospholipids and phosphatases, which are activated by Ca2+, Mg2+, Zn2+ and related divalent metal ions, to regulate the mineral formation within matrix vesicles synergistically, and induce the mineralization of bone matrix. Because of the similarities between Sr2+ and these ions, this project hypothesizes that: Sr2+ will competitively substitute these ions and occupy the binding sites for them, and further regulate the bone mineralization mediated by matrix vesicles. First, The transportation of Sr2+ within the matrix vesicles will be monitored. The effects of Sr2+ on mineral deposition and phase transformation will be evaluated. Second, this project will investigate the effects of Sr2+ on the expression and activities of important phosphatases (PHOSPHO1, TNAP) at the two different stages during bone mineralization in vitro and in vivo. Based on the above findings, this project will further explore the solution of bone deficient mineralization by incorporating some divalent metal ions in Sr-containing biomaterials. The achievements of this project will provide valuable guidance for the further preparation and application of Sr related biomaterials.

微量元素锶（Sr）具有促进成骨和抑制破骨的双重作用，其在骨科领域具有诱人的应用前景。已有的研究都集中在骨形成前期锶对细胞行为的调节，而很少关注沉积于骨中的锶在后期引起的骨矿化不足。成骨细胞释放的基质小泡富含多种磷脂和磷酸酶，它们被钙、镁、锌等金属离子激活后，协同调节基质小泡内磷酸钙的形成，进而引导骨基质的矿化。基于锶与上述金属离子具有相似的性质，本项目提出理论认为：锶竞争性地取代以上离子，并参与和调控基质小泡介导的骨矿化。本项目拟追踪锶在基质小泡中的转运过程，研究锶对无定型磷灰石的形成及相转化的影响；并针对在矿化过程的两个不同阶段分别起关键作用的磷酸酶（PHOSPHO1、TNAP），探讨锶对其表达及酶解活性的调节作用。在阐明机制的基础上，本项目提出在含锶生物材料中引入部分金属阳离子，以防止锶引起的骨矿化不足。本项目的开展，将为今后含锶生物材料的设计及其在骨科的应用提供科学的指引。

微量元素锶（Sr）具有促进成骨和抑制破骨的双重作用，其在骨科领域具有诱人的应用前景。已有的研究都集中在骨形成前期锶对细胞行为的调节，而很少关注沉积于骨中的锶在后期的骨矿化过程。成骨细胞释放的基质小泡富含多种磷脂和磷酸酶，它们被钙、镁、锌等金属离子激活后，协同调节基质小泡内磷酸钙的形成，进而引导骨基质的矿化。本项目优化了基质小泡的提取方法，研究了锶对碱胆磷酸酶（PHOSPHO1）的表达的影响，发现锶可促进成骨细胞PHOSPHO1的表达水平，且锶通过抑制微小RNA21（miRNA21），促进PI3K的磷酸化激活该通路来实现。本项目通过体外模拟实验研究了锶掺杂对磷灰石结晶过程的影响，结果显示无论在水热环境下还是酸性环境中，锶均促进晶体形成，提高晶体的热稳定性；而镁掺杂结果正好相反。体外模拟实验结果暗示，锶可抑制骨吸收，具有预防及治疗骨质疏松骨折的潜在价值。本项目制备了同时含有钙、锶、镁的磷灰石材料，体外细胞实验显示，通过调整合适的配比，此类材料可促进细胞的增殖，生物相容性好。本项目的开展，为后期含锶生物材料的设计及其在骨科的应用提供了科学的指引。