Analysis of functional disturbance of chondroctyes in oseoarthritis and establishment of new therapeutic strategies for the disease.

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In this research project, we employed a technique of laser microdissection on osteoarthritic (OA) and normal cartilage and performed a detailed analysis on the functional alteration of chondrocyte with the disease. The findings obtained in this project are summarized below.1.In OA cartilage, chondrocytes undergo a certain phenotypic change at the surface of degenerated areas, and the profile of matrix gene expression is altered. In those areas, the expression of cartilage matrix genes such as COL2A1 and aggrecan is suppressed, and instead, the expression of pathologically induced genes, such as COL3A1 and fibronectin, is enhanced. The change or the shift in the pattern of matrix gene expression might promote matrix loss in those areas by replacing the matrix with that of a poorer quality. Assuming this to be true, it might be possible that the progression of OA could be slowed down through the normalization of cellular functions at the surface of degenerated cartilage.2.To date, no clear explanation has been give to the contradiction in the pathology of OA that the cartilage matrix is gradually lost in spite of enhanced matrix synthesis. The result of this project revealed, for the first time, that the synthetic activity by chondrocytes could be significantly impaired thorough the loss of balance in the expression of collagen genes. Even in macroscopically intact areas in OA cartilage, the expression of type IX and type XI collagen genes was relatively reduced compared with that of type II collagen. Based on the findings of human hereditary diseases and gene-manipulated mice, the reduction of these minor collagens could lead to the deterioration of cartilage matrix quality. Thus, from current results, the loss of cartilage matrix in OA could be enhanced through the disturbed matrix synthesis in OA chondrodytes.Thus, the result of this project has revealed novel, important mechanisms in the pathology of OA.