Suppression of tumor necrosis factor-mediated apoptosis by nuclear factor kappa B-independent bone morphogenetic protein/Smad signaling

The activation of nuclear factor kappaB (NF-kappa B) plays a pivotal role i n the regulation of tumor necrosis factor (TNF)-mediated apoptosis. However , little is known about the regulation of TNF-mediated apoptosis by other s ignaling pathways or growth factors. Here, unexpectedly, we found that bone morphogenetic protein (BMP)-2 and BMP-4 inhibited TNF-mediated apoptosis b y inhibition of caspase-8 activation in C2C12 cells, a pluripotent mesenchy mal cell line that has the potential to differentiate into osteoblasts depe nding on BMP stimulation. Utilizing both a trans-dominant I kappaB alpha in hibitor of NF-kappaB expressed in C2C12 cells and I kappaB kinase beta -def icient embryonic mouse fibroblast, we show that BMP-mediated survival was i ndependent of NF-kappaB activation. Rather, the antiapoptotic activity of B MPs functioned through the Smad signaling pathway. Thus, these findings pro vide the first report of a BMP/Smad signaling pathway that can inhibit TNF- mediated apoptosis, independent of the prosurvival activity of NF-kappaB. O ur results suggest that BMPs not only stimulate osteoblast differentiation but can also promote cell survival during the induction of bone formation, offering new insight into the biological functions of BMPs.