[Truncated abstract] Osteoarthritis (OA) is the most common form of arthritis, characterized by progressively degeneration of articular cartilage. Chondrocyte is the only cell type in articular cartilage tissue and responsible for cartilage matrix turnover. This thesis focuses on the biological and genetic behaviors of human chondrocyte and potential therapeutic strategies that target on chondrocyte. Chondrocytes have been used for the tissue-engineered cartilage construction, especially in articular cartilage repair. The technique of chondrocyte-base tissue engineering utilizes in vitro propagated chondrocytes combined with several manufactured biomaterials to regenerate cartilage tissue. Although these technologies have been successfully applied in clinic, the biological characteristics of chondrocyte during in vitro propagation and after implantation remain unclear. This thesis reviewed the present studies of chondrocyte biology and its potential uses in tissue engineering. Particularly, chondrocytes have been shown to de-differentiate into fibroblastic-cells when they are exposed to inflammatory conditions or cultured on monolayer in vitro. This thesis investigated the gene expression profile of chondrocytes when they are cultured and serially passaged on monolayer in vitro. Human chondrocytes obtained from OA patients were cultured up to passage 6. Twenty-eight chondrocyte associated genes were measured by Real-time PCR. The results showed that a number of genes were changed in expression levels at various stages of passage as indications of chondrocyte de-differentiation. Chondrocytes derived from OA patients or normal donors exhibited a very similar gene expression pattern. Interestingly, transcription factor Sox-9, which plays a key role in chondrogenesis remained unchanged with increasing passage number, indicating that the de-differentiation process of chondrocyte is reversible. This thesis also focused on the development of novel pharmacological approaches for OA that target on articular chondrocyte. The clinical feature, etiology, pathogenesis, diagnostic approaches, conventional and potential future treatments for OA were briefly reviewed in this thesis. ... The effects of natural compounds on chondrocyte gene expression, proteoglycan degradation and nitric oxide production were measured. The results showed that parthenolide, a NF-kB inhibitor, regulated chondrocyte function by suppressing the up-regulation of gene expression of inflammatory factors and matrix proteinases induced by lipopolysaccharide, and down-regulating COX-2 expression. Parthenolide was able to reduce proteoglycan degradation in human chondrocytes, but had no effect on nitric oxide production. These results suggest that parthenolide mediates inflammatory-activated NF-kB pathway, and subsequently reduces inflammatory response, prevents cartilage destruction and relieves pain, and hence may be useful for OA treatment.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2007|