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Gene transfer with HSP 70 in rat chondrocytes confers cytoprotection in vitro and during experimental osteoarthritis

Laurent Grossin^*, Christel Cournil-Henrionnet^*,, Astrid Pinzano^*, Nadège Gaborit^*, Dominique Dumas, Stéphanie Etienne^*, Jean François Stoltz, Bernard Terlain^*, Patrick Netter^*, Lluis M. Mir^,1 and Pierre Gillet^*,1,2

^* Unité Mixte de Recherches 7561, Centre National de la Recherche Scientifique-Université Henri Poincaré Nancy 1, Faculté de Médecine, Vandoeuvre lès Nancy, France;
Unité Mixte de Recherche 8121 "Vectorologie et transfert de gènes" Centre National de la Recherche Scientifique, Institut Gustave-Roussy, Villejuif Cedex, France;
Unité Mixte de Recherches 7563 "Mécanique et Ingénierie cellulaire et tissulaire" (LEMTA), Centre National de la Recherche Scientifique, Université Henri Poincaré Nancy 1, Faculté de Médecine, Vandoeuvre lès Nancy, France

²Correspondence: Unité Mixte de Recherches 7561, Centre National de la Recherche Scientifique-Université Henri Poincaré Nancy 1, Faculté de Médecine, Ave. de la Forêt de Haye, BP184, F-54505 Vandoeuvre lès Nancy, France. E-mail: Pierre.Gillet{at}medecine.uhp-nancy.fr

Osteoarthritis is characterized by a gradual degradation of extracellular matrix, resulting from an excess of chondrocyte cell death, mainly due to an increase in apoptotis. Recent studies have revealed the essential role of HSP70 in protecting cells from stressful stimuli. Therefore, overexpressing HSP70 in chondrocytes could represent a good strategy to prevent extracellular matrix destruction. To this end, we have developed a vector carrying HSP70/GFP, and transduced chondrocytes were thus more resistant to cell death induced by mono-iodoacetate (MIA). To overcome the barrier-effect of matrix, we investigated the efficacy of plasmid delivery by electroporation (EP) in rat patellar cartilage. Two days after EP, 50% of patellar chondrocytes were HSP/GFP+. After 3 months, long-term expression of transgene was only depicted in the deep layer (20–30% positive cells). HSP70 overexpression inhibited the natural endochondral ossification in the deep layer, thus leading to a lesser decrease in chondrocyte distribution. Moreover, overexpression of HSP70, after a preventive EP transfer in rat patella, was sufficient to decrease the severity of osteoarthritis-induced lesions, as demonstrated histologically and biochemically. In conclusion, intracellular overexpression of HSP70, through EP delivery, could protect chondrocytes from cellular injuries and thus might be a novel chondroprotective modality in rat OA.—Grossin, L., Cournil-Henrionnet, C., Pinzano, A., Gaborit, N., Dumas, D., Etienne, S., Stoltz, J. F., Terlain, B., Netter, P., Mir, L. M., Gillet, P. Gene transfer with HSP 70 in rat chondrocytes confers cytoprotection in vitro and during experimental osteoarthritis.

Key Words: gene delivery • patellar cartilage • apoptosis • MIA

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