Role of proprotein convertases in the regulation of osteoblast functions

前蛋白转化酶在成骨细胞功能调节中的作用

• 批准号: RGPIN-2016-05213
• 负责人: Ferron, Mathieu
• 金额: $ 2.26万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630040
• 关键词: Role; proprotein; convertases; regulation; osteoblast

Most vertebrates possess a mineralized internal skeleton, a unique organ that allowed the evolution of articulated limbs and the conquest of continents by tetrapodes more then 300 millions years ago. Bones are formed and maintained through the process of ossification, which implicates the action of a highly specialized cell type: the osteoblast. This cell, which exists only in bony vertebrates, possesses the exclusive capacity to synthesize and secrete the proteins composing the bone extracellular matrix and to induce the mineralization of this matrix. The genetic program directing the formation and the activity of osteoblasts has been extensively studied over the past 20 years. However, the biochemical and enzymatic processes implicated in the capacity of osteoblasts to secrete extracellular matrix proteins remain poorly understood. Hence, we are proposing in our research program to study in the osteoblast the functions of proprotein convertases, a family of enzymes, which cut hundreds of other secreted proteins, either activating or inactivating them. This process is also called protein maturation. Like other secretory cells, osteoblasts function most likely depends on the maturation of several secreted proteins, yet the role of proprotein convertases in osteoblasts has only been superficially studied so far. To understand the role played by proprotein convertases in ossification, our laboratory takes advantage of the most widely used vertebrate model organism, the mouse. Using genetic tools developed in this organism, we will engineer modified mice lacking specific proprotein convertases only in osteoblasts. We will then characterize the bones of these animals to unravel the role of these enzymes in bone matrix formation and mineralization. Our laboratory also masters techniques to study osteoblast function outside of the organism in cell culture. These approaches will allow us to better appreciate the cellular and biochemical role played by proprotein convertases in osteoblast function. This research program is important to understand how protein maturation by proprotein convertases in osteoblasts controls ossification. It will also generate novel knowledge on this aspect of osteoblast biology and therefore make important contributions to this field.

大多数脊椎动物都拥有矿化的内部骨骼，这是一种独特的器官，可以进化出铰接的四肢，并在3亿年前被四足动物征服大陆。骨骼是通过骨化过程形成和维持的，这涉及到一种高度特化的细胞类型：成骨细胞的作用。这种细胞仅存在于骨脊椎动物中，具有合成和分泌构成骨细胞外基质的蛋白质并诱导该基质矿化的独特能力。在过去的20年里，指导成骨细胞形成和活性的遗传程序已被广泛研究。然而，与成骨细胞分泌细胞外基质蛋白的能力有关的生化和酶促过程仍然知之甚少。因此，我们建议在我们的研究计划中研究成骨细胞中前蛋白转化酶的功能，这是一种酶家族，可以切割数百种其他分泌蛋白，激活或灭活它们。这个过程也被称为蛋白质成熟。与其他分泌细胞一样，成骨细胞的功能很可能依赖于几种分泌蛋白的成熟，但到目前为止，成骨细胞中前蛋白转化酶的作用仅得到了初步研究。为了了解前蛋白转化酶在骨化中所起的作用，我们的实验室利用了最广泛使用的脊椎动物模式生物小鼠。利用这种生物体中开发的遗传工具，我们将设计只在成骨细胞中缺乏特定前蛋白转化酶的改良小鼠。然后，我们将描述这些动物的骨骼，以揭示这些酶在骨基质形成和矿化中的作用。我们的实验室还掌握了在细胞培养中研究生物体外成骨细胞功能的技术。这些方法将使我们能够更好地了解前蛋白转化酶在成骨细胞功能中所起的细胞和生化作用。这项研究计划对于了解成骨细胞中蛋白质前体转化酶的蛋白质成熟如何控制骨化具有重要意义。它也将产生新的知识，在这方面的成骨细胞生物学，因此作出重要贡献，这一领域。