1. HIF-1[alpha] metabolically controls collagen synthesis and modification in chondrocytes
- Author
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Stegen, Steve, Laperre, Kjell, Eelen, Guy, Rinaldi, Gianmarco, Fraisl, Peter, Torrekens, Sophie, and Van Looveren, Riet
- Subjects
Cartilage cells -- Physiological aspects ,Osteochondrodysplasias -- Risk factors -- Genetic aspects ,Glutamine metabolism -- Physiological aspects ,Transcription factors -- Physiological aspects ,Bone development -- Genetic aspects ,Physiological research ,Glutamine ,Dysplasia ,Hydroxylation ,Oxidation-reduction reactions ,Proline ,Proteases ,Post-translational modifications ,Collagen ,Lysine ,Fibrosis ,Glucose ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Endochondral ossification, an important process in vertebrate bone formation, is highly dependent on correct functioning of growth plate chondrocytes.sup.1. 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 environment.sup.1,2. In addition, the centre of the expanding growth plate becomes hypoxic, and local activation of the hypoxia-inducible transcription factor HIF-1[alpha] is necessary for chondrocyte survival by unidentified cell-intrinsic mechanisms.sup.3-6. It is unknown whether there is a requirement for restriction of HIF-1[alpha] signalling in the other regions of the growth plate and whether chondrocyte metabolism controls cell function. Here we show that prolonged HIF-1[alpha] 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 [alpha]-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-1[alpha] 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.Increased glutamine metabolism caused by unregulated HIF-1[alpha] signalling in mouse chondrocytes results in increased post-translational modification of collagen and skeletal dysplasia, demonstrating that strict regulation of HIF-1[alpha] signalling in chondrocytes is essential for normal bone growth., Author(s): Steve Stegen [sup.1] , Kjell Laperre [sup.1] , Guy Eelen [sup.2] [sup.3] , Gianmarco Rinaldi [sup.4] [sup.5] , Peter Fraisl [sup.2] [sup.3] , Sophie Torrekens [sup.1] , Riet Van [...]
- Published
- 2019
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