Intérêt de la vectorisation et/ou de l'induction des protéines de stress dans les modèles expérimentaux de pathologies ostéoarticulaires : Validation de l'électroporation biphasique

Abstract : During articular diseases, chondrocytes suffer different mechanisms which take part in the degradation of the cartilage, either by generating cell death by apoptosis (without renewal of extracellular matrix components), or by protease activation which destroy matrix components. Based on the cytoprotective potential of Heat Shock proteins (Hsp70 and Hsp27) during degenerative diseases, we evaluated the therapeutic interest of these proteins induced by a transient proteasome inhibitor (MG132), in an experimental model, by transection of the anterior cruciate ligament (ACLT). During this study, we have evaluated a new electroporation system to overexpress HSPs in articular cartilage. This technique is based on two sets of electric pulses, wich have two roles, to permeabilize the target and to transport DNA across the permeabilized membrane. We have developed expression vectors to generate a fusion protein (Hsps linked to GFP). Effectively, GFP permit to detect simply the fusion protein in the targeted tissue by fluorescence. Besides, we have evaluated safety and efficiency of electric pulses on healthy and alterated tissues (degenerative and inflammatory). We have reported that this technique could limit articular tissue damages and, moreover, could offer the ability to target more specifically this tissue. Indeed, this apparatus allows a great number of electrics pulses combinations (number, frequency, intensity). Finally, the effects of the induction via MG132 of Hsps in a physiopathological ACLT model, have been evaluated and we have shown a decrease of severity of joint lesions, in cartilage and synovial tissues. This molecule has the advantage to reinforce the resistance of chondrocytes at stressful stimuli and moreover, to limite the amplitude of inflammatory response which contribute to the magnification of extracellular matrix destruction.
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Nadège Gaborit. Intérêt de la vectorisation et/ou de l'induction des protéines de stress dans les modèles expérimentaux de pathologies ostéoarticulaires : Validation de l'électroporation biphasique. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2008. Français. ⟨NNT : 2008NAN10127⟩. ⟨tel-01777270⟩

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