Telomerase and Chondrocyte Life-Span and Differentiation

Thomas Jefferson University, Philadelphia PA

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Abstract

Chondrocytes are terminally differentiated cartilagespecific cells that are responsible for the production and assembly of the abundant extracellular matrix (ECM) of all cartilaginous tissues including articular cartilage. It has long been known that once damaged, articular cartilage has a very limited repair capability. This is exemplified in joint diseases such as osteoarthritis (OA) where the chondrocyte repair response appears to be finite. Emerging procedures to treat such diseases invblve ex vivo manipulation and expansion of autologous chondrocytes for re-implantation into focal defects or, in the future, re- surfacing of joints. Alternatively, slowing or stopping the break down process by delivery of a protective agent, such as an inhibitor or gene product, is also being heavily explored. Since OA is primarily a disease of older individuals, aging of chondrocytes in vivo may contribute to the disease pathology. Chondrocytes with a reduced capacity for division may not be able to efficiently partake in the reparative process. Furthermore, chondrocytes isolated from older patients may be deficient in their ability to proliferate in culture making it less feasible to use them in autologous transplant or gene therapy regimes. It has long been known that human diploid cells have a finite life-span in culture and eventually enter senescence, a state where the cells no longer divide. A similar situation is thought to exist in vivo, contributing, at least in part, to the process of aging. During the proliferative phase in culture, human diploid cells lose telomere length and evidence has shown that this loss controls the entry into senescence. Recently, it has been demonstrated that expression of telomerase in certain human diploid cells greatly extends their life-span in vitro without resulting in the types of changes associated with transformed or malignant cells. This extension of life-span is presumably afforded by the maintenance or stabilization of telomere length. These results have brought forth the notion that some types of human primary cells made to express telomerase, and thereby gain an extended life-span, might be useful in treating diseases related to aging and also for autologous cell and gene therapy procedures. Therefore, we intend to test the hypothesis that expression of human telomerase in human chondrocytes will extend their life-span and explore the effect of expression of telomerase on the chondrocyte phenotype.