Einfluss des „Hepatocyte Growth Factor“ (HGF) auf die Sekretion der Matrix -Metalloproteinasen (MMP) 1- und 3 sowie der Tissue Inhibitors of Metalloproteinases (TIMP) 1- und 2 bei Kniegelenkssynovialfibroblasten bei der Osteoarthrose

Die Synovialfibroblasten sind neben den Chondrozyten und den Makrophagen/Monozyten zusammen mit den MMPs und den TIMPs bekanntermaßen an der Pathogenese der Osteoarthrose beteiligt. HGF ist als morphogenetischer Wachstumsfaktor bekannt und spielt bei vielen degradierenden Prozessen eine Rolle. Der E...

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Bibliographic Details
Main Author: Bögemann, Martin
Contributors: Tibesku, Carsten (Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2008
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It is known that synovial fibroblasts, next to chondrocytes and macrophages/monocytes promote the pathogenesis of osteoarthrosis together with MMPs and TIMPs. HGF is a morphogenetic growth factor that is involved in many degredating processes. The impact of HGF on MMPs and TIMPs has so far not been surveyed in the case of osteoarthrosis. Objective: The intention of this thesis was to investigate the effect on HGF on the expression of MMPs and TIMPs by synovial fibroblasts in synovial tissue and in synovial liquid in Osteoarthrosis of the knee. Method: Synovial liquid and cartilage of the knees of 41 patients with Osteoarthrosis was collected and synovial fibroblasts and chondrocytes cultivated, expanded and stimulated. The relationship between the concentration of HGF in synovial liquid and the degree of osteoarthrosis was to be shown by the means of Enzyme Linked Immuno Sorbent Assay (ELISA). The Polymerase Chain Reaction (PCR) was used to provide evidence for the transcription of HGF and its receptor c-Met in synovial fibroblasts. The confinement of the MMPs to those relevantly regulated by HGF was done with PCR as well. The detection of the activity of proteases of the relevant proMMPs -1 and -3 was established by Cymography. Finally the quantitative impact of HGF on the secretion of the MMPs -1 and -3 and of the TIMPs -1 and -2 by tissue- and liquid-synovial fibroblasts was investigated by ELISA. Results: The HGF-ELISA showed an increasing HGF-concentration in synovial liquid with rising degree of severity of osteoarthrosis. So HGF plays a certain role with osteoarthrosis of the knee. The HGF- and c-Met-Transcription in synovial fibroblasts was confirmed. Thus synovial fibroblasts are a place of origin and effect of HGF. The MMPs -1 and -3 are concentration dependently regulated by HGF and in contrast to MMP -8 and -13, which are not, continued to be examined. Pro-MMP -1 and -3 show proteolytic activity especially in liquid synovial fibroblasts. The quantitative analysis of the secretion of MMP -1 and -3 by synovial fibroblasts after stimulation by HGF proved a statistically significant dose-dependent increase of MMP -1 and -3 (p < 0,001). HGF does not regulate TIMP -1 and -2 in a dose-dependent way. Conclusion: Next to the well known cytokines (e.g. IL-1β or TNF-α), HGF seems to be involved in the pathogenesis of osteoarthrosis by inducing MMP -1 and -3 which are established within the desease’s development. This thesis underlines the importance of the role that synovial fibroblasts play in the pathogenesis of osteoarthrosis.