(Taken from the application): Several recent studies have documented that articular chondrocytes die by apoptosis and that the apoptotic index of' articular cartilage increases with age in rats and mice. Chondrocyte death has been associated with osteoarthritis in both animal and human studies. While there are numerous animal models available for the study of cartilage degeneration, there are currently no models available to address the outcome of primary chondrocyte death. In addition, there are no models available that allow for the specific killing of chondrocytes in a temporally restricted manner in vivo, which would be quite useful for studying the repair response of cartilage to this type of lesion. We propose to create and characterize a transgenic mouse model of primary chondrocyte death by expressing the Herpes simplex virus thymidine kinase (HSVtk) gene in articular chondrocytes. We have constructed an expression vector in which the HSVtk gene is under the control of promoter and enhancer elements from the rat type II collagen gene that confer high-level cartilage-specific expression. Following the integration of this construct as a transgene, chondrocytes could be killed selectively at any point in the animal's life by administration of the anti-viral drug ganciclovir.
The Specific Aims of this proposal are: (1) Create transgenic mice expressing the CII-HSVtk transgene. (2) Establish the relationship between the chondrocyte cell death and the degeneration of articular cartilage under several drug treatment regimens in multiple lines of transgenics. (3) Establish the time course of chondrocyte death and cartilage degeneration and the repair potential of the cartilage. This model will be useful for testing the hypothesis that the death of articular chondrocytes can be the initiating event in degenerative cartilage disease. It will also allow for the study of the repair response of the cartilage following the induction of varying degrees of chondrocyte cell death. Although it is not possible to predict the exact level of chondrocyte cell death or the precise response of the cartilage in this model, we feel fl~at the potential usefulness of such a transgenic line is well worth a preliminary test of feasibility.
