The general hypothesis proposes that age-related changes in chondrocytes and a decompensation of repair function increase susceptibility to the development of Osteoarthritis (OA). This project will study aging of human articular cartilage. During the course of the project, cartilage will be obtained from more than 500 donors. These tissues will be subjected to detailed morphometric, biochemical, cell biological, biomechanical and molecular biological analysis. This will provide a large database on aging of human cartilage and allow the different projects in this program to examine specific structural and functional properties of this tissue and its cells during the aging process. We have not introduced models of cartilage repair into the program with the primary objective to study the age-associated performance of intrinsic repair mechanisms and at the same time to define age effects on novel approaches to assist cartilage repair with bioengineered materials. This part of the program will thus add to the scientific foundation of therapeutic cartilage repair. The program has 3 cores (administration, tissue and morphology) and the following 4 projects: Project 1 (PI, M. Lotz): Age-related changes in cartilage cellularity, chondrocyte death and the presence of apoptotic bodies in cartilage. Functional properties of apoptotic bodies will be examined and the relationship between apoptotic bodies and matrix vesicles will be determined. Project 2 (PI, R. Terkeltaub): Articular cartilage shows an increased incidence of crystal deposition in order individuals. Recent progress in the understanding of CPPD crystal formation was provided by the identification of the plasma cell protein-1 (PC-1) as a pyrophosphate-generating enzyme with nucleoside triphosphate pyrophosphohydrolase activity. This now allows, for the first time, to address molecular mechanisms that are involved with this aspect of cartilage aging. Project 3 (PI, D> Amiel): A system has been developed that uses polylactic acid (PLA) carries to deliver perichondrial cells as a source of chondroprogenitors to successfully heal full thickness cartilage defects. This will be used as a model to determine the effect of aging on cartilage repair in skeletally mature versus aged rabbits. Perichondrial cells will be transfected with TGFbeta1 or PC-1 to address the role of these proteins in the repair of cartilage lesions. Long-term repair of defects in mature versus old animals will be studies after implantation of PLA scaffold alone or with perichondrial cells with or without TGFbeta1 transfection. Project 4 (PI. R. Sah): This project will define age-related changes in biomechanical properties of cartilage and correlate this with biochemical analyses. The effect of donor age, TGFbeta and PC-1 on cartilage formation by human perichondrial cells and chondrocytes will be determined. Cellular responses to mechanical stimulation have been characterized and this will be used as a model to assess age effects on the cellular responses to mechanical stimulation. The integration of resident cartilage and repair tissue is critical for the outcome of cartilage repair and this project will determine tensile, adhesive and fracture properties and perform a detailed biochemical analysis of specific matrix components in this interface.
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