Hypoxia and HIF-1 alpha in chondrogenesis.

In endochondral bone development chondrocytes undergo well-ordered and controlled phases of proliferation, hypertrophic differentiation, mineralization of the surrounding matrix, death, blood vessel invasion, and finally replacement of cartilage with bone. The chondrocytic growth plate is a unique mesenchymal tissue, as it is avascular but it requires blood vessel invasion, i.e. the angiogenic switch, in order to be replaced by bone. We have recently provided evidence that the growth plate is hypoxic during fetal development. Adaptation to hypoxia is a critical event in numerous pathological settings, such as tumor progression and survival of tissues in which blood flow has been suddenly interrupted. One of the hallmarks of the response to hypoxia is activation of the transcription factor HIF-1alpha. The von Hippel Lindau tumor suppressor protein VHL is a component of a ubiquitin ligase promoting proteolysis of HIF-1alpha. By using a genetic approach, we have demonstrated the essential role of the hypoxia/VHL/HIF-1alpha pathway in endochondral bone development. Hypoxia-dependent up regulation of HIF-1alpha transcriptional activity is critical for survival of hypoxic chondrocyte, and it shapes up the fetal growth plate by inhibiting chondrocyte proliferation, increasing matrix accumulation and probably modulating cell size. The findings overall highlight the usefulness of studying fetal growth plate development as a model to address issues such as adaptation of normal tissues to hypoxia, survival of hypoxic cells, and regulation of the angiogenic switch. They also demonstrate a crucial role of hypoxia and HIF-1alpha in development and differentiation.