RESUMO
Thiazolidinediones (TZD), a class of anti-diabetic drugs, determine bone loss and increase fractures particularly in post-menopausal women, thus suggesting a protective role of sex steroids. We have previously demonstrated that the TZD rosiglitazone (RGZ) negatively affects bone mass by inhibiting osteoblastogenesis, yet inducing adipogenesis, in bone marrow-derived human mesenchymal stem cells (hMSC). The aim of this study was to determine whether estrogens and androgens are able to revert the effects of RGZ on bone. hMSC express estrogen receptor α and ß and the androgen receptor. We found that 17ß-estradiol (10 nM), the phytoestrogen genistein (10 nM), testosterone (10 nM) and the non-aromatizable androgens dihydrotestosterone (10 nM) and methyltrienolone (10 nM) effectively counteracted the adipogenic effect of RGZ (1 µM) in hMSC induced to differentiate into adipocytes, as determined by evaluating the expression of the adipogenic marker peroxisome proliferator-activated receptor γ and the percentage of fat cells. Furthermore, when hMSC were induced to differentiate into osteoblasts, all the above-mentioned molecules and also quercetin, another phytoestrogen, significantly reverted the inhibitory effect of RGZ on the expression of the osteogenic marker osteocalcin and decreased the number of fat cells observed after RGZ exposure. Our study represents, to our knowledge, the first demonstration in hMSC that androgens, independently of their aromatization, and estrogens are able to counteract the negative effects of RGZ on bone. Our data, yet preliminary, suggest the possibility to try to prevent the negative effects of TZD on bone, using steroid receptor modulators, such as plant-derived phytoestrogens, which lack evident adverse effects.
Assuntos
Adipogenia/efeitos dos fármacos , Androgênios/farmacologia , Estrogênios/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Tiazolidinedionas/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Adipogenia/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/fisiologia , RosiglitazonaRESUMO
Thiazolidinediones (TZD) are widely prescribed for the treatment of Type 2 diabetes. Increased loss of bone mass and a higher incidence of fractures have been associated with the use of this class of drugs in post-menopausal women. In vitro studies performed in rodent cell models indicated that rosiglitazone (RGZ), one of the TZD, inhibited osteoblastogenesis and induced adipogenesis in bone marrow progenitor cells. The objective of the present study was to determine for the first time the RGZ-dependent shift from osteoblastogenesis toward adipogenesis using a human cell model. To this purpose, bone marrow-derived mesenchymal stem cells were characterized and induced to differentiate along osteogenic and adipogenic lineages. We found that the exposure to RGZ potentiated adipogenic differentiation and shifted the differentiation toward an osteogenic phenotype into an adipogenic phenotype, as assessed by the appearance of lipid droplets. Accordingly, RGZ markedly increased the expression of the typical marker of adipogenesis fatty-acid binding protein 4, whereas it reduced the expression of Runx2, a marker of osteoblastogenesis. This is the first demonstration that RGZ counteracts osteoblastogenesis and induces a preferential differentiation into adipocytes in human mesenchymal stem cells.
Assuntos
Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Tiazolidinedionas/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Modelos Biológicos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , RosiglitazonaRESUMO
PURPOSE: Sacral bone remodelling with abnormal dilatation of intervertebral foramina is usually associated with Tarlov cysts but can be caused by slow-growth lesions, which also may present cerebrospinal-fluid (CSF)-like signal or density. We describe three patients with a similar history of lower back pain presenting CSF-like density/signal lesions with extensive sacral bone remodelling who were affected by a Tarlov cyst, an epidermoid cyst and a giant neurofibroma, respectively. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) studies were performed with 1.0-T magnet; axial and sagittal pre- and postcontrast T1-and T2-weighted images were obtained. Moreover, axial and sagittal diffusion-weighted (DWI) echoplanar images were produced, and corresponding apparent diffusion coefficient (ADC) values were calculated. ADC values were measured within the lesions on axial images. RESULTS: All lesions presented a CSF-like signal on conventional MRI. The Tarlov cyst was hypointense on DWI with high ADC values (2,793 s/mm(2)+/-137). The epidermoid cyst proved to be markedly hyperintense on DWI, with reduced ADC values (855 s/mm(2)+/-109). The neurofibroma was isointense on DWI, with ADC values not compatible with CSF (1,467 s/mm(2)+/-130). CONCLUSIONS: DWI and ADC values seem to be able to clearly differentiate Tarlov cysts from slow-growth lesions, allowing for adequate treatment.