The production of collagen – a major component of the extracellular matrix – depends on hydroxylation of proline residues, a reaction that uses molecular oxygen as substrate. Cells that develop in hypoxic settings can nevertheless produce collagen during embryogenesis. Elazar Zelzer and colleagues begin to resolve this paradox on p. by identifying the transcription factor hypoxia-inducible factor 1 α (HIF1α) as a central regulator of collagen hydroxylation and secretion by chondrocytes in the hypoxic growth plate of developing mouse bones. The researchers show that Hif1a loss of function in growth plate chondrocytes arrests the secretion of collagen. Hif1α, they report, drives the transcription of collagen prolyl 4-hydroxylase, which mediates collagen hydroxylation and its subsequent folding and secretion. Concurrently, Hif1α also maintains cellular oxygen levels, probably by controlling the expression of pyruvate dehydrogenase kinase 1, an inhibitor of the tricarboxylic acid cycle. This two-pronged mechanism, the researchers suggest, allows chondrocytes to secrete large amounts of collagen in the hypoxic environment of the growth plate.
