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Overexpression and induction of heat shock protein 70 protect chondrocytes from cell death in vitro and in vivo
Arthritis Res Ther volume 5, Article number: 53 (2003)
Osteoarthritis (OA) is characterized by fibrillation and erosion of hyaline cartilage, subchondral bone sclerosis and osteophyte formation at the joint margins. These changes, resulting from poorly understood events, lead to both cartilage matrix degradation and inhibition of matrix component synthesis. Moreover, cartilage hypocellularity due to cell death (apoptosis or necrosis) contributes to the development of OA. Heat shock protein 70 (Hsp70) plays a protective role as a molecular chaperone in cells by facilitating the folding, intracellular transport, assembly, and disassembly of proteins. An increase in the expression of Hsp70 in chondrocytes has been associated with the severity of OA lesions and could be an indicator of the early stages of OA. Some experiments recently demonstrated that Hsp70 protects cells from death induced by stresses, mechanical and biological factors.
To determine whether Hsp70 overexpression is able to protect rat chondrocytes towards mono-iodoacetate (MIA) cytotoxicity, in vitro and in vivo.
Induction of Hsp70 was performed with MG132, a proteasome inhibitor, and overexpression of Hsp70 was realized by the non-viral gene transfer method. The chondroprotective effect of Hsp70 was assessed in vitro by exposing cells to MIA and the protection was determined by MTT/lactate dehydrogenase analyses. An antisense strategy was used to confirm that Hsp70 played the major role in protecting chondrocytes from MIA toxicity. In a second step, the relevance of a preventive induction or overexpression of Hsp70 was assessed in vivo, during experimental OA in the rat induced by intra-articular injection of MIA.
In vitro, the increase of Hsp70 by proteasome inhibitor exposure or by gene transfer was able to efficiently protect chondrocytes from MIA toxicity. The antisense strategy confirmed that Hsp70 mainly mediated this chondroprotective effect. In vivo, the induction (intra-articular injection of MG132) or overexpression of Hsp70 (electric gene transfer) was sufficient to decrease the severity of the OA-lesions induced by MIA exposure, as demonstrated by histological and biochemical analyses.
Overexpression of Hsp70 in cartilage could be an interesting way to protect in vitro chondrocytes from cell death and to reduce in vivo the progression of OA-related chondral erosions.
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Grossin, L., Cournil-Henrionnet, C., Watrin-Pinzano, A. et al. Overexpression and induction of heat shock protein 70 protect chondrocytes from cell death in vitro and in vivo. Arthritis Res Ther 5, 53 (2003) doi:10.1186/ar854
- Heat Shock Protein
- Proteasome Inhibitor
- Hyaline Cartilage
- Bone Sclerosis
- Gene Transfer Method