Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells.

Bone morphogenetic protein (BMP)-2, a member of the transforming growth factor-beta (TGF-beta) superfamily, is able to induce osteoblastic differentiation of C2C12 cells. Both Smad and mitogen-activated protein kinase (MAPK) pathways are essential components of the TGF-beta superfamily signaling machinery. Although Smads have been demonstrated to participate in the BMP-2-induced osteoblastic differentiation of C2C12 cells, the role of MAPK has not been addressed. This report shows that BMP-2 activates ERK and p38, but not JNK, in C2C12 cells. Pretreatment of cells with the p38 inhibitor, SB203580, dramatically reduced BMP-2-induced expression of the osteoblast markers alkaline phosphatase (ALP) and osteocalcin (OC). Nevertheless, overexpression of MKK3, a protein kinase that phosphorylates and activates p38, failed to induce ALP or OC expression in the absence of BMP-2, indicating that p38 activation is necessary but not sufficient for the acquisition of the osteoblast phenotype by these cells. Although ALP induction was increased slightly in the presence of PD-98059, a selective inhibitor of the ERK cascade, this compound significantly inhibited both steady-state and BMP-2-induced OC RNA levels. Our results indicate that p38 and ERK cascades play a crucial role in the osteoblast differentiation of C2C12 cells mediated by BMP-2.

[Effect of cardiac rate on the index of feto-placental circulatory resistance]. / Effet de la fréquence cardiaque sur l'index de résistance circulatoire foeto-placentaire.

Variations of the fetal heart rate in normal or pathological fetuses may induce significant changes of the Doppler indices widely used for the evaluation and the assessment of the placental or cerebral resistances. In case of a low heart rate (120/mn for example), the end diastolic amplitude will be weaker than in case of a heart rate of high frequency (160/mn). This phenomena may explain the great scattering of the normal values of the Doppler indices and the relatively poor sensitivity of this parameter. We tried to minimize the effect of the heart rate on the evaluation of the doppler indices by two methods. Firstly by measuring on the maximum frequency curve the end diastolic frequency for a standard heart rate of 140/mn and the corresponding Doppler index (R'140). Secondly by using a formula giving directly (from the R value on the trace) the value of the index (R"140) for a heart rate of 140/mn. The diagrams of the indices (R'140 R"140) calculated for a standard frequency of 140/mn (on normal and pathological fetuses) show a greater dispersion than the R indices directly measured on the Doppler waveform. Therefore, the sensitivity and the specificity of the Doppler method are reduced. Finally, we conclude that the haemodynamic parameters in the different vascular areas of the fetus can adapt to the heart rate except for very strong abnormalities of the heart rate as it is the case in atrio ventricular blocks for instance. Out of these cases, it seems that the normalization of the index by the heart rate does not improve the accuracy of the doppler indices.