OSMOLARITY AND CHONDROCYTE MECHANOTRANSDUCTION

渗透压和软骨细胞机械传导

• 批准号: 6791836
• 负责人: Clare E Yellowley-Genetos
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791836
• 关键词: biological signal transduction; calcium flux; cell growth regulation; cell morphology; chloride channels; chondrocytes; cyclic AMP; mechanical stress; membrane channels; osmotic pressure; potassium channel; prostaglandin E

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.

描述（摘自应用程序）： 背景：一直显示影响软骨的一个因素 生物合成是机械负荷，是正常的结果 关节运动。然而，软骨细胞的物理环境是复杂的 在机械加载期间，尚不清楚哪些物理信号 软骨细胞做出反应。在这项研究中，我们将重点关注渗透的潜力 改变以充当相关的细胞信号。在机械加载过程中 当液体被迫进入软骨细胞时，软骨细胞的渗透环境受到干扰 循环地脱离基质，增加和减少局部蛋白聚糖 浓度，因此，离子强度和渗透压。渗透压变化 已在其他细胞类型中显示可激活膜转运途径 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，这些功能的激活是可能的 信号事件也可能构成机械传导机制的一部分 由此，机械负荷被转化为代谢反应。 假设：我们的中心假设是细胞外渗透压的变化， 由机械负荷诱导，调节软骨细胞生物合成 通过参与音量调节的信号机制。目的：本研究中 我们的目标是确定低渗透压对细胞内钙的影响 (Caa2+)、腺苷 3', 5'-环单磷酸 (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 Ca2+、cAMP 和 PGE2 以及离子通道在容量调节中的激活（目标 3）和软骨细胞生物合成（目标4）。这项研究的数据将为我们提供新的 深入了解软骨细胞如何应对渗透压挑战以及能力 渗透挑战改变软骨细胞的生物合成活性。 意义：这些研究的长期目标是提高我们的 了解机械负荷如何影响生物合成行为 软骨细胞。了解机械负载等因素， 调节软骨周转，可能提供对软骨循环的深入了解 骨关节炎和类风湿性关节炎等疾病的病理生理学 提供防止软骨破裂的治疗。