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  • Title: Heat shock protein 90 maintains the tumour-like character of rheumatoid synovial cells by stabilizing integrin-linked kinase, extracellular signal-regulated kinase and protein kinase B.
    Author: Hashiramoto A, Murata M, Kawazoe T, Yoshida K, Akiyama C, Shiozawa K, Shiozawa S.
    Journal: Rheumatology (Oxford); 2011 May; 50(5):852-61. PubMed ID: 21177334.
    Abstract:
    OBJECTIVE: To clarify the contribution of heat shock protein 90 (HSP90) to the pathogenesis of RA, we studied the effects of geldanamycin (GA), an inhibitor of HSP90, on excessive cellular extension and resistance to apoptosis induction of rheumatoid synovial cells. METHODS: Expression of integrin-α5β1 and integrin-linked kinase (ILK) in synovial cells was determined by western blot. The peripheral localization of ILK, reorganization of F-actin, complex formation of ILK with particularly interesting new cysteine-histidine protein (PINCH) and α-parvin, and activation of Rac/cdc42 in synovial cells were examined by using immunohistochemistry and immunoprecipitation. Apoptosis induction by GA treatment was analysed by nuclear staining, cell proliferation assay and western blot of caspase. Effects of GA on mitogen-activated protein kinase (MAPK), PI-3K/protein kinase B (Akt) pathway, mitochondrial Bcl-2 pathway and activation of nuclear factor-κB (NF-κB) were examined by western blot and ELISA. RESULTS: HSP90 was overexpressed in synovial cells while GA decreased the expression of integrin-α5β1 and ILK. The peripheral localization of ILK, reorganization of F-actin, complex formation of ILK with PINCH and α-parvin, and activation of Rac/cdc42 in synovial cells were all inhibited by GA treatment. We found that HSP90 stabilized and regulated the MAPK and PI-3K/Akt pathway, thereby inhibiting HSP90-potentiated synovial apoptosis by stimulating caspases and the mitochondrial Bcl-2 pathway on the one hand and inhibiting the activation of NF-κB on the other. CONCLUSION: The contribution of HSP90 is important in the pathogenesis of RA that potentiates a tumour-like synovial overgrowth by stabilizing ILK, extracellular signal-regulated kinase and Akt.
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