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: 6267390
• 负责人: Robert L Sah
• 金额: $ 19.92万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6267390
• 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.

骨关节炎是影响腹泻的最常见的人类疾病