Functional Properties of Extracellular Matrix

细胞外基质的功能特性

• 批准号: 6432511
• 负责人: PETER J. BASSER
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432511
• 关键词: biophysics; body water dehydration; cartilage; chemical models; collagen; extracellular matrix; human tissue; mechanical stress; model design /development; osmotic pressure; osteoarthritis; physical model

The collagen network plays a critical role in determining functional properties of cartilage and other extracellular matrices. The collagen network exerts a retractive stress on the osmotically active proteoglycans trapped within it in much the same way a balloon's rubber membrane exerts a hydrostatic pressure of the gas contained within it. Until now, however, it has not been possible to measure important physical properties of the collagen network independently of other constituents within the extracellular matrix. Recently, we devised a new methodology to determine structural properties of the collagen network per se, such as its bulk modulus. This new approach entails (a) modeling the cartilage tissue matrix as a composite material consisting of two distinct phases: a collagen network and a proteoglycan (PG) solution trapped within it, (b) applying various known levels of equilibrium osmotic stress, and (c) using physical-chemical principles and independent experiments to determine useful "pressure-volume" relations for both the PG and collagen phases independently. In pilot studies, we used this approach to determine pressure-volume curves for the collagen network and the PG phases in native and in trypsin treated normal human cartilage specimen, as well as in cartilage specimen from osteoarthritic (OA) joints. In both normal and trypsin-treated specimen, collagen network stiffness appeared unchanged,whereas in the OA specimen, collagen network stiffness decreased. Our findings highlight the role of the collagen network in limiting normal cartilage hydration, and in ensuring a high PG concentration in the matrix, both of which are essential for effective load bearing in cartilage, but are lost in OA. These data also suggest that the loss of collagen network stiffness, and not the loss or modification of PGs may be the incipient event leading to the subsequent disintegraton of cartilage observed in OA. Recently, Kimberlee Potter has initiated microscopic Magnetic Resonance Imaging (MRI) studies designed to estimate parameters of our mathematical model of cartilage swelling noninvasively by attempting to relate the chemical composition of cartilage tissue grown in a hollow-fiber bioreactor to various measurable MRI parameters. Ferenc Horkay is now developing an instrument that will enable us to study swelling properties of extremely thin cartilage sections, permitting us to obtain a profile its functional properties with depth from a joint's articular surface.

胶原网络在决定软骨和其他细胞外基质的功能特性中起着关键作用。胶原蛋白网络对被困在其中的具有渗透活性的蛋白聚糖施加了一个缩回应力，这与气球的橡胶膜对其中所含气体施加静水压力的方式非常相似。然而，直到现在，还不可能独立于细胞外基质中的其他成分来测量胶原网络的重要物理特性。最近，我们设计了一种新的方法来确定胶原蛋白网络本身的结构特性，例如它的体积模量。这种新方法需要(a)将软骨组织基质建模为由两种不同相组成的复合材料：胶原蛋白网络和其中捕获的蛋白聚糖（PG）溶液，(b)应用各种已知的平衡渗透应力水平，以及(c)使用物理化学原理和独立实验来确定PG和胶原蛋白相的有用的“压力-体积”关系。在初步研究中，我们使用这种方法来确定天然和胰蛋白酶处理的正常人类软骨标本以及骨关节炎（OA）关节软骨标本中胶原网络和PG相的压力-体积曲线。在正常和胰蛋白酶处理的标本中，胶原网络刚度没有变化，而在OA标本中，胶原网络刚度下降。我们的研究结果强调了胶原网络在限制正常软骨水化和确保基质中PG浓度高方面的作用，这两者对于软骨的有效承重都是必不可少的，但在OA中却缺失了。这些数据还表明，胶原网络刚度的丧失，而不是pg的丧失或修饰，可能是导致骨性关节炎软骨随后解体的早期事件。最近，Kimberlee Potter发起了显微磁共振成像（MRI）研究，旨在通过尝试将中空纤维生物反应器中生长的软骨组织的化学成分与各种可测量的MRI参数联系起来，估计我们的无创软骨肿胀数学模型的参数。Ferenc Horkay现在正在开发一种仪器，使我们能够研究极薄软骨部分的肿胀特性，使我们能够从关节表面的深度获得其功能特性的轮廓。