OSMOLARITY AND CHONDROCYTE MECHANOTRANSDUCTION

描述(取自申请表)： 背景：一直被证明影响软骨的一个因素 生物合成是机械负荷，是正常情况下发生的结果 联合动议。然而，软骨细胞的物理环境是复杂的 在机械加载期间，还不清楚是哪种物理信号 软骨细胞会做出反应。在这项研究中，我们将重点放在渗透的潜力上 改变以充当相关的细胞信号。在机械加载期间 当液体被强迫进入软骨细胞时，软骨细胞的渗透环境受到扰动。 循环地排出基质，增加和减少局部蛋白多糖 浓度，因此，离子强度和渗透压。渗透性变化 已经在其他类型的细胞中显示了激活膜转运途径和 作为体积的一部分增加细胞内信号因子的水平 监管回应。然而，激活这些组件是可能 信号事件也可能构成机械转导机制的一部分。 将机械负荷转化为代谢反应。 假设：我们的中心假设是细胞外渗透压的变化， 由于机械负荷将诱导，调节软骨细胞的生物合成 通过参与音量调节的信号机制。目标：在这项研究中 我们的目标是确定低渗透压对细胞内钙的影响。 (CaA2+)、3‘，5’-环磷酸腺苷(CAMP)和前列腺素E2 (PGE2)水平(目标1)，离子通道激活(目标2)，并检查 钙离子、环磷酸腺苷和前列腺素E_2与离子通道激活的容量调节(目的 3)和软骨细胞生物合成(目标4)。这项研究的数据将给我们带来新的 深入了解软骨细胞如何应对渗透挑战，以及 改变软骨细胞的生物合成活性的渗透挑战。 意义：这些研究的长期目标是增加我们的 了解机械负荷如何影响生物合成行为 软骨细胞。了解各种因素，例如机械负荷， 调节软骨周转，可能潜在地提供对 骨关节炎和类风湿性关节炎等疾病的病理生理学和 提供防止软骨破裂的治疗方法。

DESCRIPTION (Taken from the application): Background: One factor which is consistently shown to influence cartilage biosynthesis is mechanical loading, which occurs as a consequence of normal joint motion. However, the physical environment of the chondrocyte is complex during mechanical loading and it is unclear to which physical signals chondrocytes respond. In this study we will focus on the potential for osmotic change to act as a relevant cellular signal. During mechanical loading the osmotic environment of the chondrocyte is perturbed as fluid is forced into and out of the matrix cyclically, increasing and decreasing local Proteoglycans concentrations and therefore, the ionic strength and osmolarity. Osmotic change has been shown in other cell types to activate membrane transport pathways and increase levels of intracellular signaling factors as part of a volume regulatory response. It is possible, however, that activation of these signaling events might also form part of a mechanotransduction mechanism whereby mechanical loads are transduced into a metabolic response. Hypothesis: Our central hypothesis is that changes in extracellular osmolarity, as would be induced by mechanical loading, regulate chondrocyte biosynthesis through signaling mechanisms involved in volume regulation. Aims: In this study our goal is to determine the effect of hypo-osmolarity on intracellular calcium (Caa2+), adenosine 3', 5'-cyclic monophosphate (cAMP) and prostaglandin E2 (PGE2) levels (Aim 1), ion channel activation (Aim 2), and examine the role of Ca2+, cAMP and PGE2 and ion channel activation in both volume regulation (Aim 3) and chondrocyte biosynthesis (Aim 4). Data from this study will give us new insight into how chondrocytes contend with osmotic challenge, and the ability of osmotic challenge to modify the biosynthetic activity of chondrocytes. Significance: The long term goal of these studies is to increase our understanding of how mechanical loading influences the biosynthetic behavior of chondrocytes. An understanding of factors, such as mechanical load, which regulate cartilage turnover, could potentially provide insights into the pathophysiology of diseases such as osteoarthritis and rheumatoid arthritis and provide treatments which prevent cartilage breakdown.