Fetal growth plate: a developmental model of cellular adaptation to hypoxia

Fetal growth plate chondrocyte is a unique mesenchymal tissue, as it is avascular and hypoxic. Yet, chondrocytes not only survive in this environment, but also undergo all cellular processes (proliferation, growth arrest, differentiation, etc.) required for normal endochondral bone development. A crucial mediator of the adaptive response of cells to hypoxia is a transcription factor named hypoxia-inducible factor 1alpha (Hif-1alpha). One target of Hif-1alpha transcriptional activation is the angiogenic factor vascular endothelial growth factor (VEGF), whereas Hif-1alpha accumulation is controlled by the von Hippel-Lindau (VHL) tumor suppressor, an E3-ubiquitin ligase that induces its degradation by the proteasome. We, and others, demonstrated that each component of this pathway is a critical regulator of endochondral bone development. In particular, we previously established that Hif-1alpha is a survival factor for hypoxic chondrocytes, and that it also negatively regulates cell proliferation. Interestingly, we also showed that hypoxia increases extracellular matrix accumulation in a Hif-1alpha-dependent fashion. This suggested that Hif-1alpha could be critically important not only for cell survival and proliferation but also for cell differentiation. We recently demonstrated that Hif-1alpha is indeed a differentiation factor since it is required in mesenchymal cells both for early chondrogenesis, and for joint development.