RESUMO
The rate of endochondral bone growth determines final height in humans and is tightly controlled. Glycogen synthase kinase-3 (GSK-3) is a negative regulator of several signaling pathways that govern bone growth, such as insulin/IGF and Wnt/ß-catenin. The two GSK-3 proteins, GSK-3α and GSK-3ß, display both overlapping and distinct roles in different tissues. Here we show that pharmacological inhibition of GSK-3 signaling in a mouse tibia organ culture system results in enhanced bone growth, accompanied by increased proliferation of growth plate chondrocytes and faster turnover of hypertrophic cartilage to bone. GSK-3 inhibition rescues some, but not all, effects of phosphatidylinositide 3-kinase inhibition in this system, in agreement with the antagonistic role of these two kinases in response to signals such as IGF. However, cartilage-specific deletion of the Gsk3b gene in mice has minimal effects on skeletal growth or development. Molecular analyses demonstrated that compensatory up-regulation of GSK-3α protein levels in cartilage is the likely cause for this lack of effect. To our knowledge, this is the first tissue in which such a compensatory mechanism is described. Thus, our study provides important new insights into both skeletal development and the biology of GSK-3 proteins.
Assuntos
Cartilagem/enzimologia , Quinase 3 da Glicogênio Sintase/metabolismo , Tíbia/enzimologia , Aminofenóis/farmacologia , Animais , Western Blotting , Cartilagem/metabolismo , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Feminino , Deleção de Genes , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/metabolismo , Imuno-Histoquímica , Masculino , Maleimidas/farmacologia , Camundongos , Camundongos Knockout , Técnicas de Cultura de Órgãos , Fosfatidilinositol 3-Quinases/metabolismo , Tíbia/efeitos dos fármacos , Tíbia/crescimento & desenvolvimento , Regulação para Cima , beta Catenina/metabolismoRESUMO
Is the administration of oral antibiotics four times a day as necessary as some pharmacokinetic studies indicate? The efficacy of cephalexin administered twice a day was compared to the same drug administered four times a day for the treatment of skin and skin structure infections due to staphylococcus and/or streptococcus. The 154 outpatients in this four-clinic study ranged in age from 1 month to more than 70 years. A random number table was used to assign patients to either the twice a day or the four times a day regimen. The total daily dosage was the same in each regimen. Administration twice a day proved equally effective to the four times a day regimen. Both regimens were more than 97 percent effective and side effects were minimal.
