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HIF-1? metabolically controls collagen synthesis and modification in chondrocytes.

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-1? is necessary for chondrocyte survival by unidentified cell-intrinsic mechanisms3-6. It is unknown whether there is a requirement for restriction of HIF-1? signalling in the other regions of the growth plate and whether chondrocyte metabolism controls cell function. Here we show that prolonged HIF-1? 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 ?-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? 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.

SUBMITTER: Stegen S

PROVIDER: S-EPMC7195049 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Stegen Steve S Laperre Kjell K Eelen Guy G Rinaldi Gianmarco G Fraisl Peter P Torrekens Sophie S Van Looveren Riet R Loopmans Shauni S Bultynck Geert G Vinckier Stefan S Meersman Filip F Maxwell Patrick H PH Rai Jyoti J Weis MaryAnn M Eyre David R DR Ghesquière Bart B Fendt Sarah-Maria SM Carmeliet Peter P Carmeliet Geert G

Nature 20190116 7740

Endochondral ossification, an important process in vertebrate bone formation, is highly dependent on correct functioning of growth plate chondrocytes<sup>1</sup>. 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</sup>. In addition, the centre of the expanding growth plate becomes hypoxic, and local activation of t ...[more]

PMID: 30651640

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Project description:Osteoarthritic (OA) chondrocytes are shown to express inducible nitric oxide synthase (iNOS) which produces high concentrations of nitric oxide (NO), particularly when stimulated with proinflammatory cytokines. NO is involved in OA cartilage degradation. On the other hand, c-Jun N-terminal Kinase (JNK) pathway mediates the activation and transcription of c-Jun, which is required for interleukin-1 (IL-1)-induction of matrix metalloproteinases-13 (MMP-13) in OA pathogenesis. Therefore, the selective inhibition of iNOS and c-Jun is a promising target for treatment and prevention of OA. The purpose of the study was to investigate the inhibitory effects of pentosan polysulfate (PPS) on IL-1β-induced iNOS, c-Jun and HIF-α isoforms upregulation in canine articular chondrocytes (CACs). Primary (P0) chondrocytes were isolated and cultured from femoral head cartilages of three (3) dogs. First passage (P1) chondrocytes were preincubated with 0, 1, 5, 15 and 40 μg/mL of PPS for 4 hr before treatment with 10 ng/mL rhIL-1β for a further 8 hr. In addition, we evaluated the effects of single and multiple cytokine with or without LPS on iNOS protein induction. PPS significantly inhibited (P < 0.05) IL-1β-induced iNOS, c-Jun and HIF-1α mRNA upregulation in a dose-dependent pattern. iNOS mRNA was significantly inhibited at 15 and 40 μg/mL whereas c-Jun and HIF-1α were significantly downregulated at 5, 15 and 40 μg/mL of PPS compared to chondrocytes treated with only rhIL-1β. Intriguingly, CACs were recalcitrant to single IL-1β, TNF-α or LPS-induction of iNOS protein including to a combination of IL-1β+TNF-α, IL-1β+LPS except to TNF-α+LPS and IL-1β+TNF-α+LPS suggestive of a protective mechanism from iNOS detrimental effects on perpetuating OA. IL-1β+TNF-α+LPS-induced iNOS protein expression was significantly abrogated by PPS. We demonstrate for the first time that PPS is a novel inhibitor of IL-1β-induced iNOS, c-Jun, and HIF-1α mRNA upregulation and iNOS protein induction which may be beneficial for prevention and treatment OA.

Dataset Information

HIF-1? metabolically controls collagen synthesis and modification in chondrocytes.

Publications

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

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