Long‐term treatment of swiss 3T3 fibroblasts with dexamethasone attenuates MAP kinase activation induced by insulin‐like growth factor‐I (IGF‐I)

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Abstract
Bone formation is reduced in hyperglucocorticoid states, e.g. Cushing's syndrome or long-term treatment with synthetic glucocorticoids during rheumatic diseases. Possibly related to decreased sensitivity of the target to insulin-like growth factor-I (IGF-I). In this study, we have sought to identify postreceptor-mechanisms for glucocorticoid-induced resistance to insulin-like peptides in a model system. Treatment of Swiss 3T3 fibroblasts with 100 nM dexamethasone for 48 h reduced IGF-I-induced activation of mitogen-activated protein kinase (MAP kinase). The level of insulin receptor substrate-1 (IRS-1) was reduced in dexamethasone-treated cells, as measured by Western blot; however, the pattern of tyrosine-phosphorylated protein subsequent to stimulation with IGF-I (1 min) was not altered. No inhibitory effect of dexamethasone was observed on the level of phosphotyrosine in IRS-1 in extracts from IGF-I-treated cells. The amount of IGF-I-induced association of insulin receptor substrate-1 and phosphatidylinositol 3-kinase was increased in steroid treated cells. Addition of IGF-I increased the synthesis of lipid, glycogen and protein, and the reduction of a tetrazolium dye, MTS, in untreated cells. The response to IGF-I in terms of glycogen synthesis was blunted, whereas the effect of IGF-I was unaffected for the other three parameters in cells pretreated with dexamethasone. These findings indicate that the activation of MAP kinase may be dissociated from IGF-I-induced anabolic pathways and tyrosine phosphorylationof IRS-1. The results agree with the previously proposed role for the activation of MAP kinase in the regulation of glycogen synthesis. Furthermore, they suggest that dexamethasone-induced reduction of IRS-1 expression may be important for the impaired activation of MAP kinase by insulin-like peptides in steroid-treated cells.
Funding Information
  • Magnus Bergvalls FoundationNovo Nordisk Foundation