HIF-1α metabolically controls collagen synthesis and modification in chondrocytes

Nature. 2019 Jan;565(7740):511-515. doi: 10.1038/s41586-019-0874-3. Epub 2019 Jan 16.


Endochondral ossification, an important process in vertebrate bone formation, is highly dependent on correct functioning of growth plate chondrocytes1. Proliferation of these cells determines longitudinal bone growth and the matrix deposited provides a scaffold for future bone formation. However, these two energy-dependent anabolic processes occur in an avascular environment1,2. In addition, the centre of the expanding growth plate becomes hypoxic, and local activation of the hypoxia-inducible transcription factor HIF-1α is necessary for chondrocyte survival by unidentified cell-intrinsic mechanisms3-6. It is unknown whether there is a requirement for restriction of HIF-1α signalling in the other regions of the growth plate and whether chondrocyte metabolism controls cell function. Here we show that prolonged HIF-1α signalling in chondrocytes leads to skeletal dysplasia by interfering with cellular bioenergetics and biosynthesis. Decreased glucose oxidation results in an energy deficit, which limits proliferation, activates the unfolded protein response and reduces collagen synthesis. However, enhanced glutamine flux increases α-ketoglutarate levels, which in turn increases proline and lysine hydroxylation on collagen. This metabolically regulated collagen modification renders the cartilaginous matrix more resistant to protease-mediated degradation and thereby increases bone mass. Thus, inappropriate HIF-1α signalling results in skeletal dysplasia caused by collagen overmodification, an effect that may also contribute to other diseases involving the extracellular matrix such as cancer and fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Diseases / metabolism*
  • Bone Diseases / pathology*
  • Cartilage / metabolism
  • Chondrocytes / metabolism*
  • Collagen / biosynthesis*
  • Extracellular Matrix / metabolism
  • Glucose / metabolism
  • Glutamine / metabolism
  • Growth Plate / metabolism
  • Hydroxylation
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / deficiency
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics
  • Ketoglutaric Acids / metabolism
  • Lysine / metabolism
  • Male
  • Mice
  • Osteogenesis
  • Oxidation-Reduction
  • Proline / metabolism


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ketoglutaric Acids
  • Glutamine
  • Collagen
  • Proline
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Glucose
  • Lysine