RESUMO
The proteins of the hedgehog (Hh) family regulate various aspects of development. Recently, members of this family have been shown to regulate skeletal formation in vertebrates and to control both chondrocyte and osteoblast differentiation. In the present study, we analyzed the effect of Sonic hedgehog (Shh) on the osteoblastic and adipocytic commitment/differentiation. Recombinant N-terminal Shh (N-Shh) significantly increased the percentage of both the pluripotent mesenchymal cell lines C3H10T1/2 and ST2 and calvaria cells responding to bone morphogenetic protein 2 (BMP-2), in terms of osteoblast commitment as assessed by measuring alkaline phosphatase (ALP) activity. This synergistic effect was mediated, at least partly, through the positive modulation of the transcriptional output of BMPs via Smad signaling. Furthermore, N-Shh was found to abolish adipocytic differentiation of C3H10T1/2 cells both in the presence or absence of BMP-2. A short treatment with N-Shh was sufficient to dramatically reduce the levels of the adipocytic-related transcription factors C/EBPalpha and PPARgamma in both C3H10T1/2 and calvaria cell cultures. Given the inverse relationship between marrow adipocytes and osteoblasts with aging, agonists of the Hh signaling pathway might constitute potential drugs for preventing and/or treating osteopenic disorders.
Assuntos
Adipócitos/citologia , Diferenciação Celular , Linhagem da Célula , Mesoderma/citologia , Mesoderma/metabolismo , Proteínas de Neoplasias , Osteoblastos/citologia , Transativadores/metabolismo , Fator de Crescimento Transformador beta , Adipócitos/efeitos dos fármacos , Adipócitos/enzimologia , Adipócitos/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Proteína Morfogenética Óssea 2 , Proteínas Morfogenéticas Ósseas/farmacologia , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteínas de Transporte , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Linhagem da Célula/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sinergismo Farmacológico , Indução Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog , Mesoderma/efeitos dos fármacos , Mesoderma/enzimologia , Camundongos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/enzimologia , Osteoblastos/metabolismo , Osteocalcina/genética , Regiões Promotoras Genéticas/genética , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Crânio/citologia , Proteínas Smad , Transativadores/genética , Transativadores/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína GLI1 em Dedos de ZincoRESUMO
The non-steroidal antiandrogens, RU 58841 and RU 56187 are amongst the most active of a new series of N-substituted aryl hydantoins or thiohydantoins. Their pharmacokinetics and principal metabolic profiles have been evaluated in rat plasma after intravenous administration of a 10 mg/kg dose. Both compounds disappear relatively rapidly from the plasma (elimination half-life of the order of 1 h), but they form a common metabolite, the N-desalkyl derivative, RU 56279, which is eliminated much more slowly. The percentage transformations of each into RU 56279, estimated from the AUCs of the metabolite compared with the AUC obtained after administration of RU 56279 itself, were respectively 1% and 77%. In parallel, their in vivo activity, as well as that of their metabolites, was determined with respect to parameters related to systemic antiandrogenic effects (prostate and seminal vesicle weights). The results showed that: (1) the common metabolite, RU 56279, is clearly antiandrogenic; (2) there appears to be a relationship between the percentage formation of this metabolite and the systemic antiandrogenic activity of the compounds. Thus, the pharmacological profile of RU 58841 which displays a potent local antiandrogenic activity without systemic effects can be related to its very low propensity to form the N-desalkyl metabolite.
