A role for annexin V in bone cell mechanotransduction

描述（由申请人提供）：已知骨骼的物理环境在建立和维持结构称职的骨骼中起重要作用。然而，物理信号发挥这种生物效应的机制尚不清楚。虽然生物物理信号在骨细胞中引起各种细胞反应，但这些反应的启动机制尚不清楚。在这项研究中，我们提出膜联蛋白V (AnxV)，一种CA2+依赖性磷脂结合蛋白，是启动机械转导所需的关键蛋白。AnxV具有许多特性，这表明它非常适合作为一种机械感受器，可能是一种机械敏感离子通道。这些包括作为Ca2+选择性膜离子通道的功能，以及与细胞外基质蛋白（如胶原蛋白）和细胞骨架元素（如肌动蛋白）相互作用的能力。

DESCRIPTION (provided by applicant): The physical environment of the skeleton is known to play an important role in the establishment and maintenance of structurally competent bone. However, the mechanisms by which physical signals exert such biological effects are unclear. While biophysical signals elicit a variety of cellular responses in bone cells, the mechanism by which these responses are initiated is unknown. In this study we propose that annexin V (AnxV), a CA2+-dependent phospholipid binding protein, is a critical protein required for initiating mechanotransduction. AnxV has a number of attributes, which suggest that it is ideally suited for a role as a mechanoreceptor, possibly a mechanosensitive ion channel. These include the ability to function as a Ca2+ selective membrane ion channel, and the ability to interact with both extracellular matrix proteins such as collagen, and cytoskeletal elements such as actin. Hypothesis: our central hypothesis is that bone cells detect and transduce physical signals into biological responses via a mechanism requiring AnxV. Aims: Our goal is test this hypothesis by determining the role of AnxV in the response of bone cells to oscillating fluid flow, a physiologically relevant physical signal in bone. We will determine whether AnxV, in a role as a Ca2+ selective, mechanosensitive ion channel, is required for flow-induced Ca2+ influx, global increases in Ca2+i and ultimately gene expression in human osteoblast-like MG63 cells and murine osteocytic MLO-Y4 cells (Aims 1, 2 and 3). We will also determine whether expression and cellular location of AnxV are regulated by fluid flow (Aim 4). Significance: The long-term goal of these studies is to increase our understanding of how biophysical signals are selected and converted into an appropriate biological response by bone cells. Identification of critical "mechanotransducer" proteins may also provide novel targets for future therapeutic interventions in the fight against bone diseases such as osteoporosis.