Citrate Metabonegenic Regulation for the next Generation of Orthopedic Biomaterial Design

研究总结 这个项目的目标是阐明一种未被探索的柠檬酸对骨的代谢调控。 发展，并将这些认识转化为新型仿生柠檬酸盐呈现物的设计 骨科应用的骨生物材料。尽管在以下方面取得了重大进展： 骨科生物材料的发展，目前可用的材料由于不能模拟而受到限制 天然组织成分，机械强度弱，成骨活性低，炎症明显 反应差，骨整合差，骨再生慢。我们假设细胞外的摄取 柠檬酸通过转运蛋白SLC13a5通过调节细胞代谢来提高细胞的能量状态， 这进而通过抑制AMP激活的活性而促进成骨表型进展 蛋白激酶(AMPK)。这种以柠檬酸盐为基础的新的骨骼发育调节被称为柠檬酸盐。 代谢调控(图1)。确定新的和未探索的基于柠檬酸盐的策略来 促进间充质干细胞成骨分化可被利用来更有效地设计 下一代仿生骨科生物材料，以解决以前材料的局限性。至 验证我们的假设，实现本项目的目标，提出三个目标：目标1)阐明 柠檬酸对骨髓间充质干细胞成骨分化的代谢调控作用 对柠檬酸分子机理在仿生柠檬酸盐生物材料设计中的认识 诱导骨髓间充质干细胞分化；目的3)评价骨髓间充质干细胞在体内的解剖学和化学性能 模拟柠檬酸呈递支架在大鼠颅骨缺损模型中的应用。非常耐人寻味的是 对尚未探索的柠檬酸盐机理的前所未有的了解将使我们能够设计出下一个 生成仿生动态整形植入物，该植入物可以在 细胞和组织发育。对骨干细胞柠檬酸代谢调控的认识 培养和动态骨材料设计不仅将促进骨组织工程领域的发展，而且还将促进骨组织工程的发展。 深刻影响一系列其他条件，如MSC成脂分化，因为MSCs是 多能性和成脂分化也有很高的能量需求。

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.