Citrate Metabonegenic Regulation for the next Generation of Orthopedic Biomaterial Design

研究综述 本项目的目的是阐明柠檬酸盐对骨代谢的调节作用 发展，并将这些理解转化为新的仿生柠檬酸盐呈递的设计， 骨生物材料用于矫形外科应用。虽然在这方面取得了重大进展， 骨科生物材料的发展，目前可用的材料是有限的，他们无法模仿 天然组织成分、弱机械强度、最小骨诱导性、显著炎性 反应，骨整合差和骨再生慢。我们假设细胞外的摄取 柠檬酸盐通过转运蛋白SLC 13 a5可以通过调节细胞代谢来提高细胞能量状态， 这反过来又通过抑制AMP活化的 蛋白激酶（AMPK）。这种新的以柠檬酸盐为基础的调节骨发育的作用被称为柠檬酸盐 代谢产物调控（图1）。确定新的和未探索的基于柠檬酸盐的策略， 促进间充质干细胞的成骨分化可以被利用来更有效地设计 下一代仿生骨科生物材料，以解决以前的材料的局限性。到 为了验证我们的假设并实现本项目的目标，提出了三个目标：目标1）阐明 柠檬酸盐对MSCs成骨分化的代谢调节作用;目的2）应用 仿生柠檬酸盐递呈生物材料设计中柠檬酸盐分子机理的认识 目的3）从解剖学和化学上评价细胞的体内性能， 模拟柠檬酸盐呈递支架在大鼠临界尺寸颅骨缺损模型中的应用。非常有趣的是， 关于未探索的柠檬酸盐机制的前所未有的知识将使我们能够设计下一个 仿生动态骨科植入物的产生， 细胞和组织发育。柠檬酸盐对骨干细胞代谢调控的认识 培养和动态骨材料设计不仅将推动骨组织工程领域的发展， 深刻地影响了广泛的其他条件，如MSC成脂分化，因为MSC是 多能和成脂分化也具有高能量需求。

Research Summary The objectives of this project are to elucidate an unexplored metabonegenic regulation of citrate for bone development, and to translate these understandings towards the design of novel biomimetic citrate-presenting bone biomaterials for orthopedic applications. Although significant progress has been made in the development of orthopedic biomaterials, the currently available materials are limited by their inabilities to mimic the native tissue composition, weak mechanical strength, minimal osteoinductivity, significant inflammatory responses, poor bone integration, and slow bone regeneration. We hypothesize that the uptake of extracellular citrate via transporter SLC13a5 could elevate cellular energy status through modulation of cell metabolism, which in turn leads to a facilitated osteogenic phenotype progression by inhibiting the activity of AMP-activated protein kinase (AMPK). This new citrate-based regulation of bone development is referred to as citrate metabonegenic regulation (Fig. 1). The identification of new and unexplored citrate-based strategies to promote osteogenic differentiation of mesenchymal stem cell can be harnessed to more efficiently design the next generation of biomimetic orthopedic biomaterials to address the limitations of the previous materials. To test our hypotheses and achieve the objectives of this project, three aims are proposed: Aim 1) to elucidate the metabonegenic regulatory effect of citrate for MSCs osteogenic differentiation; Aim 2) to apply the understandings of the citrate molecular mechanism in the design of biomimetic citrate-presenting biomaterials to mediate MSCs differentiation; Aim 3) To evaluate the in vivo performance of anatomically and chemically mimetic citrate-presenting scaffolds in a rat critically sized cranial bone defect model. It is very intriguing that the unprecedented knowledge on the unexplored citrate mechanism will enable us to design the next generation of biomimetic dynamic orthopedic implants that may present citrate signals in demand during cellular and tissue development. The understanding on the citrate metabonegenic regulation for bone stem cell culture and dynamic bone materials design will not only advance the field of bone tissue engineering, but also profoundly impact a wide array of other conditions such as MSC adipogenic differentiation since MSCs is multipotent and the adipogenic differentiation also has high energy demand.