Transcription mechanism of chondrogenesis

The precise patterning of a developing skeletal framework relies on appropriate control of chondrogenesis and on subsequent cartilage development. This multistep process, where mesenchymal cells differentiate into chondrocytes and then chondrocytes progress though each developmental zone of the cartilage, is tightly regulated by a number of key signaling molecules, which include PTH-related protein, fibroblast growth factor, bone morphogenetic protein and transforming growth factor. Importantly, these factors have been shown to promote phosphorylation of transcription factor cAMP response element (CREB) at its Ser133, which activates specific gene expression with recruitment of its transcriptional co-activator CREB binding protein (CBP). Recently, CBP has been shown to have intrinsic histone acetyl transferase activity, which suggests a potential link between gene expression and chromatin acetylation. In this regard, the important role of CBP in CREB-dependent gene expression has been demonstrated using a novel in vitro chromatinized template transcription assay.

With these findings, the importance of the CREB/CBP transcription complex for chondrogenesis was examined by expressing a potent dominant-negative CREB inhibitor (A-CREB). Consistent with the robust Ser133 phosphorylation of CREB during chondrogenesis, A-CREB blocked chondrogenesis from mesenchymal stem cells. During chondrogenesis, specific chromatin factors are activated by the CREB/CBP pathway and the chromatin factors promote chondrocyte-specific gene expression via association with multiple transcription factors that are known to be involved in chondrocyte differentiation. These findings suggest that, in addition to DNA-binding type transcription factors, chromatin factors, which alter the chromatin code, may play a critical role for cell differentiation and tissue-specific gene expression in cartilage development.