MAP kinase signaling cascades and gene expression in osteoblasts

Environmental cues direct osteoblasts to proliferate and differentiate. The mitogen-activated protein (MAP) kinase pathways provide a key link between the membrane bound receptors that receive these cues and changes in the pattern of gene expression. The three MAPK cascades in mammalian cells are: the extracellular signal-regulated kinase (ERK) cascade, the stress activated protein kinase/c-jun N-terminal kinase (SAPK/JNK) cascade and the p38MAPK/RK/HOG cascade. Each has varied roles, depending upon the cell type and context, that include transmitting stress, growth, differentiative and apoptotic signals to the nucleus. These pathways target an overlapping set of transcription factors that lead to the differential activation of rapid response genes, particularly members of the fos and jun family of proto-oncogenes. These proteins are the principal components of the transcription factor AP-1, which plays a central role in regulating genes activated early in osteoblast differentiation. We discuss in detail a) the nature and activation of these pathways b) how they induce c-fos expression and c) how these MAPK cascades can differentially regulate the activity of AP-1 and thereby osteoblast-specific gene expression.