The developmental control of osteoblast-specific gene expression: Role of specific transcription factors and the extracellular matrix environment

Bone formation is a carefully controlled developmental process involving mo rphogen-mediated patterning signals that define areas of initial mesenchyme condensation followed by induction of cell-specific differentiation progra ms to produce chondrocytes and osteoblasts. Positional information is conve yed via gradients of molecules, such as Sonic Hedgehog that are released fr om cells within a particular morphogenic field together with region-specifi c patterns of hox gene expression. These, in turn, regulate the localized p roduction of bone morphogenetic proteins and related molecules which initia te chondrocyte- and osteoblast-specific differentiation programs. Different iation requires the initial commitment of mesenchymal stem cells to a given lineage, followed by induction of tissue-specific patterns of gene express ion. Considerable information about the control of osteoblast-specific gene expression has come from analysis of the promoter regions of genes encodin g proteins like osteocalcin that are selectively expressed in bone. Both ge neral and tissue-specific transcription factors control this promoter. Osf2 /Cbfa1, the first osteoblast-specific transcription factor to be identified , is expressed early in the osteoblast lineage and interacts with specific DNA sequences in the osteocalcin promoter essential for its selective expre ssion in osteoblasts. The OSF2/CBFA1 gene is necessary for the development of mineralized tissues, and its mutation causes the human disease, cleidocr anial dysplasia. Committed osteoprogenitor cells already expressing Osf2/Cb fa1 must synthesize a collagenous ECM before they will differentiate. A cel l ECM interaction mediated by integrin-type cell-surface receptors is essen tial for the induction of osteocalcin and other osteoblast-related proteins . This interaction stimulates the binding of Osf2/Cbfa1 to the osteocalcin promoter through an as-yet-undefined mechanism.