AGING HUMAN ARTICULAR CARTILAGE--BIOMECHANICS AND REPAIR

老化的人类关节软骨——生物力学与修复

• 批准号: 6311469
• 负责人: Robert L Sah
• 金额: $ 20.72万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311469
• 关键词: aging; articular cartilage; biomechanics; cartilage development; cartilage metabolism; collagen; human tissue; proteoglycan; tissue /cell culture; transforming growth factors

Osteoarthritis is the most common human disease affecting diarthrodial joints, and becomes increasing prevalent during aging. The long-term goal of this project is to further the molecular-level understanding of (1) the biomechanical function of human articular cartilage during aging and osteoarthritis, and (2) the functional repair of aging and diseased human articular cartilage. With aging, human articular cartilage undergoes a decrease in cell density, an increase in calcium- containing crystals, an increase in anionic glycosaminoglycan content, and changes in the collagen meshwork (increases in denatured collagen and pentosidine cross-links). The variation in these tissue components may underlie age- and depth-dependent variations in the compressive, tensile, and fracture mechanical properties of articular cartilage. Composition-function relationships will be assessed and then tested by selectively altering the tissue composition (e.g., depletion of glycosaminoglycan and induction of apoptosis). Cartilage repair is dependent on active tissue metabolism. Conceptually, cartilage repair involves both the filling of sizable defects and the integration of regions of tissue in apposition. TGF-beta1 was previously identified as a potent stimulus for human chondrocyte proliferation. TGF-beta1 also stimulated chondrocyte production of nucleotide pyrophosphohydrolase (NTPPPH), which generates pyrophosphate and may affect cell metabolism and extracellular crystal deposition. Inhuman cartilage, NTPPPH activity is due primarily to the membrane glycoprotein, PC-1. Age-related decreases in chondrocyte proliferative and secretory responses as well as changes in responsiveness to TGF-beta1 and elaboration of PC-1/NTPPPH may affect the ability of aging cells to mount a repair response. To test this possibility, the age-related role of TGF-beta1 in regulating cartilaginous tissue formation by chondrocytes or perichondrial cells within a polylactic acid scaffold during long-term culture in vitro will be assessed; also, the effect of overexpression of PC-1 will be determined. Further, the matrix remodeling mechanisms involved in integrative repair will be assessed using an in vitro model of cartilage explants. Finally, age-related changes in the resident chondrocytes or cartilage biomechanical properties may alter the biomechanical regulation of cell biosynthesis. To test this possibility, the biosynthetic response of full thickness human articular cartilage explants to static and dynamic loads will be assessed and related to the depth-varying physical signals. Fluid flow effects on chondrocytes will be examined independently.

骨关节炎是最常见的人类疾病影响diarthrodial 关节，并在老化过程中变得越来越普遍。长期 该项目的目标是进一步在分子水平上了解 (1)人关节软骨的生物力学功能 老化和骨关节炎，和（2）老化的功能修复， 患病的人类关节软骨 随着年龄的增长， 软骨细胞密度降低，钙离子增加， 含有晶体，阴离子糖胺聚糖含量增加， 以及胶原网络的变化（变性胶原的增加 和戊糖苷交联）。 这些组织成分的变异 可能是在压缩， 关节软骨的拉伸和断裂力学性能。 组成-功能关系将被评估，然后测试， 选择性地改变组织组成（例如，枯竭 糖胺聚糖和诱导细胞凋亡）。 腕关节修复是 依赖于活跃的组织代谢。从概念上讲，软骨修复 包括填补相当大的缺陷和整合 并置的组织区域。 TGF-β 1以前被鉴定为 作为人类软骨细胞增殖的有效刺激物。 TGF-β 1 也刺激软骨细胞产生核苷酸 焦磷酸水解酶（NTPPPH），其产生焦磷酸和 可能影响细胞代谢和细胞外晶体沉积。 非人软骨，NTPPPH活性主要是由于膜 糖蛋白，PC-1。 软骨细胞中的软骨细胞减少 增殖和分泌反应以及 对TGF-β 1的反应性和PC-1/NTPPPH的形成可能 影响老化细胞的修复反应能力。 测试 这种可能性，TGF-β 1在调节 软骨细胞或软骨膜细胞形成软骨组织 在体外长期培养过程中，聚乳酸支架内的 此外，PC-1过表达的影响将被评估。 测定 此外，涉及的基质重塑机制， 将使用软骨的体外模型评估整合修复 外植体 最后，与年龄相关的变化，在驻地软骨细胞或 软骨的生物力学性质可能会改变生物力学 调节细胞生物合成。 为了测试这种可能性， 全层人关节软骨的生物合成反应 将评估静态和动态载荷的外植体，并与 深度变化的物理信号。 流体流动对软骨细胞的影响 将被独立审查。