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

在本研究项目中，我们采用激光显微解剖技术对骨关节炎（OA）和正常软骨进行了详细的分析，并对软骨细胞的功能改变进行了详细的分析。本项目的研究结果总结如下：1。在OA软骨中，软骨细胞在退变区表面发生一定的表型改变，基质基因表达谱发生改变。在这些区域，软骨基质基因如COL2A1和聚集蛋白的表达被抑制，而病理诱导基因如COL3A1和纤维连接蛋白的表达则被增强。基质基因表达模式的改变或转移可能通过用质量较差的基质代替基质而促进这些区域的基质损失。假设这是正确的，有可能通过使退行性软骨表面的细胞功能正常化来减缓OA的进展。迄今为止，对于骨性关节炎病理上的矛盾，即尽管软骨基质合成增强，但软骨基质逐渐丢失，还没有明确的解释。本项目的结果首次揭示了软骨细胞的合成活性可能因胶原基因表达失衡而显著受损。即使在OA软骨的宏观完整区域，与II型胶原相比，IX型和XI型胶原基因的表达也相对减少。根据人类遗传性疾病和基因操纵小鼠的研究结果，这些次要胶原蛋白的减少可能导致软骨基质质量的恶化。因此，从目前的结果来看，OA软骨基质的损失可能会通过OA软骨细胞中基质合成的紊乱而加剧。因此，这个项目的结果揭示了OA病理中新的、重要的机制。

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.