Transforming growth factor-Ø in osteoarthritis : the good, the bad or the ugly
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[S.l. : s.n.]
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The aim of the research described in this thesis was to elucidate the role of endogenous growth factors during osteoarthritis (OA), a joint disease characterized by cartilage damage, new bone formation (osteophytes) and fibrosis. This was done to study the function of Transforming Growth Factor-beta (TGF-beta) and Bone Morphogenetic Proteins (BMPs) in the pathogenesis of OA and determine the deleterious and protective effects of these naturally released growth factors during OA. Our results will give direction to therapeutic use of growth factors or growth factor inhibitors. During experimentally induced OA in mice we blocked TGF-beta/BMP activity by systemic administration of scavenging receptor proteins or by adenoviral overexpression of Growth Factor inhibitors in the synovial lining of the joint. We were able to show for the first time that inhibition of Growth Factors during OA led to increased cartilage damage, proving that Growth Factors are essential for proper cartilage maintenance and protects the cartilage from damage. On the other hand, blocking of Growth Factors resulted in decreased formation of new bone formation (osteophytes) and fibrosis, which are major characteristics of OA. This shows that Growth Factors are also responsible for inducing part of OA pathology.Because TGF-beta and BMP are strong inducers of cartilage matrix synthesis and inhibit cartilage degradation they have a strong therapeutic potential. We have indeed shown that endogenous TGF-beta released during experimental OA protects articular cartilage, however, our studies also show that the same levels of these growth factors during the OA disease process are responsible for unwanted side-effects. In order to apply TGF-beta or BMP as a therapeutic means to induce cartilage repair, the growth factors should be specifically targeted to the articular cartilage. We are currently pursuing the hypothesis that a TGF-beta/BMP unresponsive synovial lining, caused by adenoviral overexpression of Growth Factor inhibitors, enables the targeting of growth factors specifically to the articular cartilage. This would fully reinstating the therapeutic potential of these growth factors
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