Regulación por glucocorticoides y vitamina D de la proliferación y la diferenciación de condrocitos de cartílago epifiseal fetal humano
SUMMARY: Circulating supraphysiologic glucocorticoid (GC) concentrations inhibit skeletal growth. Growth plate cartilage and bone are target tissues for vitamin D (Vit D) and deficiency states during infancy (rickets or VitD insensitivity) provoke growth delay. With the aim of analysing the molecular mechanisms involved in skeletal growth inhibition produced by both GC excess and VitD deficiency, as well as the interaction of VitD with GH to oppose gene expression inhibition produced by high GC concentrations, VitD effects on proliferation and gene expression were studied in chondrocytes from human fetal epiphyseal cartilage. Results: Low-dose Dx (10-9 M) maintained proliferation whereas higher concentrations dose-dependently inhibited it. A similar effect was observed with VitD. IGF-I significantly stimulated proliferation and completely opposed the inhibition produced by Dx or VitD. GH had no significant effect. The addition of GH to Dx (10-6 M) and/or VitD (10-6 M) did not limit the inhibitory effects of Dx and/or VitD. Dx dose-dependently inhibited expression of GH-IGF axis genes (IGF-I, IGFBP-3, GHR), transcription factor and matrix proteins (SOX9, COL2A1, aggrecan), whereas it stimulated expression of IGF-IR and the matrix protein COMP. VitD had an opposite effect, which was also dose-dependent, by stimulating expression of IGF-I, IGFBP-3, IGF-IR, GHR and COMP, whereas it inhibited expression of SOX9, COL2A1 and aggrecan. GH alone had a variable effect, which did not reach statistical significance. VitD opposed IGF-I and GHR expression inhibition produced by Dx whereas it did not limit IGFBP-3 inhibition. The combination of VitD with GH not only completely opposed inhibition by Dx of GHR and IGF-I expression, but stimulated it. Conclusions: VitD up-regulated IGF-I, IGFBP-3, GHR and IGF-IR and COMP gene expression in human foetal epiphyseal chondrocytes. Addition of VitD to GH resulted in the highest increase in IGF-I expression. In the presence of pharmacological GC concentrations, VitD rescued IGF-I & GHR gene expression inhibition, although not IGFBP-3. Addition of VitD to GH resulted in significant stimulation of IGF-I expression, even in the presence of GC at high concentrations.
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Advisor:Audí Parera, Laura; Imperial Ródenas, Santiago; Esteban Redondo, Cristina; Carrascosa Lezcano, Antonio
School:Universitat de Barcelona
Source Type:Master's Thesis
Keywords:bioquímica i biologia molecular fac
Date of Publication:07/07/2006