A mouse's wrist has distorted and abnormally fused bones when Hif-1α is absent.

The key to building strong bones and healthy joints is oxygen scarcity in the developing embryo. As Provot et al. show on page 451, a protein activated by low oxygen levels orchestrates the formation of limb bones and joints. The work demonstrates that one function of the protein is spurring differentiation of cartilage-constructing chondrocytes.

An embryo acquires all of its oxygen via diffusion, and some parts of the body can run short. But instead of suffocating tender young cells, an oxygen shortage galvanizes them to differentiate. Low oxygen levels switch on a transcription factor called hypoxia-inducible-factor-1 (Hif-1). The researchers had previously shown that Hif-1 promotes growth and survival of chondrocytes, which sculpt a cartilage template that later fills with bone. Provot et al. wanted to determine whether the transcription factor spurs cells to specialize into chondrocytes.

The team knocked out one subunit of the protein, Hif-1α, only in limb bud mesenchyme of mice. This tissue, which spawns chondrocytes and other cell types, normally pumps out Hif-1α and is oxygen-starved. The modified mice were born with stumpy, malformed legs. As embryos, their limbs were slow to fashion cartilage, and differentiation of mesenchyme cells into chondrocytes was tardy. Moreover, large numbers of cells perished in the center of the animals' forming bones.

Limb joints are also hypoxic, and the Hif-1α–deficient mice displayed defects such as abnormally fused bones in the paws and delayed joint formation. The flaws were more severe in the wrists and ankles, which have the lowest oxygen concentrations. The findings establish that Hif-1 promotes chondrocyte differentiation and joint formation in response to hypoxia. The next step, the researchers say, is to pin down which pathways Hif-1 activates to produce these effects.