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

Steve Stegen, Kjell Laperre, Guy Eelen, Gianmarco Rinaldi, Peter Fraisl, Sophie Torrekens, Riet Van Looveren, Shauni Loopmans, Geert Bultynck, Stefan Vinckier, Filip Meersman, Patrick H. Maxwell, Jyoti Rai, MaryAnn Weis, David R. Eyre, Bart Ghesquière, Sarah-Maria Fendt, Peter Carmeliet and Geert Carmeliet ()
Additional contact information
Steve Stegen: Metabolism and Ageing, KU Leuven
Kjell Laperre: Metabolism and Ageing, KU Leuven
Guy Eelen: VIB Center for Cancer Biology, VIB
Gianmarco Rinaldi: VIB Center for Cancer Biology, VIB
Peter Fraisl: VIB Center for Cancer Biology, VIB
Sophie Torrekens: Metabolism and Ageing, KU Leuven
Riet Van Looveren: Metabolism and Ageing, KU Leuven
Shauni Loopmans: Metabolism and Ageing, KU Leuven
Geert Bultynck: Department of Cellular and Molecular Medicine, KU Leuven
Stefan Vinckier: VIB Center for Cancer Biology, VIB
Filip Meersman: Molecular and Nanomaterials, KU Leuven
Patrick H. Maxwell: University of Cambridge
Jyoti Rai: University of Washington
MaryAnn Weis: University of Washington
David R. Eyre: University of Washington
Bart Ghesquière: KU Leuven/VIB Center for Cancer Biology Leuven
Sarah-Maria Fendt: VIB Center for Cancer Biology, VIB
Peter Carmeliet: VIB Center for Cancer Biology, VIB
Geert Carmeliet: Metabolism and Ageing, KU Leuven

Nature, 2019, vol. 565, issue 7740, 511-515

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-0874-3

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