HIF-1α prevents cell death despite hypoxia (red) in a wild-type tibia.

Johnson/CSH

Randall Johnson (University of California, San Diego, CA) and colleagues have found that cells need a particular transcription factor to survive in the hypoxic interior of developing bones. The critical activity of hypoxia-inducible factor 1α (HIF-1α), they say, is probably its inductionof a glycolytic metabolism appropriate to a low oxygen environment. Without this metabolic alteration, the bone-building chondrocytes may well suffer a catastrophic drop in ATP levels that is sufficient to induce their death.

A complete knockout of HIF-1α is lethal in mice, so Schipani et al. used the CRE system to delete HIF-1α only in chondrocytes. The resulting animals had shorter limbs, defective skeletons, and massive cell death in the cartilaginous centers of their bones. In theory these changes could arise because there is no HIF-1α present to induce angiogenesis, but the mutant animals showed few changes in blood vessel growth, suggesting that a HIF-1α–independent angiogenic pathway exists. In contrast, the usual induction of glycolytic enzymes in the hypoxic regions was lost. In vitro studies using different levels of oxygenation will be needed to extend this observation beyond correlation.

The mutant animals also showed dysregulation of a cell cycle inhibitor, p57, and excess cellular proliferation. “It's quite possible that in this case hypoxia is acting as a developmental switch [to induce differentiation of proliferative cells],” says Johnson. “But that's certainly not something we have shown yet.” ▪

Reference:

Schipani, E., et al. 2001. Genes Dev. 15:2865–2876.