HIF-1α 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-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.

journal_name

Nature

journal_title

Nature

authors

Stegen S,Laperre K,Eelen G,Rinaldi G,Fraisl P,Torrekens S,Van Looveren R,Loopmans S,Bultynck G,Vinckier S,Meersman F,Maxwell PH,Rai J,Weis M,Eyre DR,Ghesquière B,Fendt SM,Carmeliet P,Carmeliet G

doi

10.1038/s41586-019-0874-3

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

511-515

issue

7740

eissn

0028-0836

issn

1476-4687

pii

10.1038/s41586-019-0874-3

journal_volume

565

pub_type

杂志文章

相关文献

NATURE文献大全
  • Structural basis for the fracture toughness of the shell of the conch Strombus gigas.

    abstract::Natural composite materials are renowned for their mechanical strength and toughness: despite being highly mineralized, with the organic component constituting not more than a few per cent of the composite material, the fracture toughness exceeds that of single crystals of the pure mineral by two to three orders of ma...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35016535

    authors: Kamat S,Su X,Ballarini R,Heuer AH

    更新日期:2000-06-29 00:00:00

  • Dynamics and number of trans-SNARE complexes determine nascent fusion pore properties.

    abstract::The fusion pore is the first crucial intermediate formed during exocytosis, yet little is known about the mechanisms that determine the size and kinetic properties of these transient structures. Here, we reduced the number of available SNAREs (proteins that mediate vesicle fusion) in neurons and observed changes in tr...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature25481

    authors: Bao H,Das D,Courtney NA,Jiang Y,Briguglio JS,Lou X,Roston D,Cui Q,Chanda B,Chapman ER

    更新日期:2018-02-08 00:00:00

  • Functional anatomy of a common semantic system for words and pictures.

    abstract::The relationship between the semantic processing of words and of pictures is a matter of debate among cognitive scientists. We studied the functional anatomy of such processing by using positron-emission tomography (PET). We contrasted activity during two semantic tasks (probing knowledge of associations between conce...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/383254a0

    authors: Vandenberghe R,Price C,Wise R,Josephs O,Frackowiak RS

    更新日期:1996-09-19 00:00:00

  • Experimental realization of the topological Haldane model with ultracold fermions.

    abstract::The Haldane model on a honeycomb lattice is a paradigmatic example of a Hamiltonian featuring topologically distinct phases of matter. It describes a mechanism through which a quantum Hall effect can appear as an intrinsic property of a band structure, rather than being caused by an external magnetic field. Although p...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature13915

    authors: Jotzu G,Messer M,Desbuquois R,Lebrat M,Uehlinger T,Greif D,Esslinger T

    更新日期:2014-11-13 00:00:00

  • Link communities reveal multiscale complexity in networks.

    abstract::Networks have become a key approach to understanding systems of interacting objects, unifying the study of diverse phenomena including biological organisms and human society. One crucial step when studying the structure and dynamics of networks is to identify communities: groups of related nodes that correspond to fun...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature09182

    authors: Ahn YY,Bagrow JP,Lehmann S

    更新日期:2010-08-05 00:00:00

  • Global patterns and predictors of marine biodiversity across taxa.

    abstract::Global patterns of species richness and their structuring forces have fascinated biologists since Darwin and provide critical context for contemporary studies in ecology, evolution and conservation. Anthropogenic impacts and the need for systematic conservation planning have further motivated the analysis of diversity...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature09329

    authors: Tittensor DP,Mora C,Jetz W,Lotze HK,Ricard D,Berghe EV,Worm B

    更新日期:2010-08-26 00:00:00

  • Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response.

    abstract::Mitochondrial genomes (mitochondrial DNA, mtDNA) encode essential oxidative phosphorylation (OXPHOS) components. Because hundreds of mtDNAs exist per cell, a deletion in a single mtDNA has little impact. However, if the deletion genome is enriched, OXPHOS declines, resulting in cellular dysfunction. For example, Kearn...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature17989

    authors: Lin YF,Schulz AM,Pellegrino MW,Lu Y,Shaham S,Haynes CM

    更新日期:2016-05-19 00:00:00

  • Unified response to bilateral hemispheric stimulation by a split-brain patient.

    abstract::Surgical sectioning of the corpus callosum in epileptic patients has provided a unique opportunity to study separately the competence and processing capacities of the two cerebral hemispheres, each of which is able to perceive, think, memorize and learn independently and essentially outside the realm of awareness of t...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/305800a0

    authors: Sergent J

    更新日期:1983-10-27 00:00:00

  • A topological Dirac insulator in a quantum spin Hall phase.

    abstract::When electrons are subject to a large external magnetic field, the conventional charge quantum Hall effect dictates that an electronic excitation gap is generated in the sample bulk, but metallic conduction is permitted at the boundary. Recent theoretical models suggest that certain bulk insulators with large spin-orb...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature06843

    authors: Hsieh D,Qian D,Wray L,Xia Y,Hor YS,Cava RJ,Hasan MZ

    更新日期:2008-04-24 00:00:00

  • Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.

    abstract::Rheumatoid arthritis is a chronic autoinflammatory disease that affects 1-2% of the world's population and is characterized by widespread joint inflammation. Interleukin-1 is an important mediator of cartilage destruction in rheumatic diseases, but our understanding of the upstream mechanisms leading to production of ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature13322

    authors: Vande Walle L,Van Opdenbosch N,Jacques P,Fossoul A,Verheugen E,Vogel P,Beyaert R,Elewaut D,Kanneganti TD,van Loo G,Lamkanfi M

    更新日期:2014-08-07 00:00:00

  • Formation of proinsulin by immobilized Bacillus subtilis.

    abstract::There has been an increasing interest in the use of immobilized cells for the production of pharmaceuticals as well as for products such as high fructose syrup or ethanol. Some of these compounds are now produced on an industrial scale whereby the cells are used in a resting or growing state or in a nonviable form as ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/302543a0

    authors: Mosbach K,Birnbaum S,Hardy K,Davies J,Bülow L

    更新日期:1983-04-07 00:00:00

  • Exon shuffling: mapping polymorphic determinants on hybrid mouse transplantation antigens.

    abstract::The mouse major transplantation antigens H-2K, H-2D and H-2L are highly polymorphic cell-surface glycoproteins which may serve as recognition elements in cell-cell interactions. Each antigen possesses a number of alloantigenic determinants defined by antisera of various specificities. Recently, monoclonal antibodies h...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/300755a0

    authors: Evans GA,Margulies DH,Shykind B,Seidman JG,Ozato K

    更新日期:1982-12-23 00:00:00

  • Reconstitution of the oocyte transcriptional network with transcription factors.

    abstract::During female germline development, oocytes become a highly specialized cell type and form a maternal cytoplasmic store of crucial factors. Oocyte growth is triggered at the transition from primordial to primary follicle and is accompanied by dynamic changes in gene expression1, but the gene regulatory network that co...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-020-3027-9

    authors: Hamazaki N,Kyogoku H,Araki H,Miura F,Horikawa C,Hamada N,Shimamoto S,Hikabe O,Nakashima K,Kitajima TS,Ito T,Leitch HG,Hayashi K

    更新日期:2021-01-01 00:00:00

  • Signal-sequence recognition by an Escherichia coli ribonucleoprotein complex.

    abstract::Hydrophobic signal-sequences direct the transfer of secretory proteins across the inner membrane of prokaryotes and the endoplasmic reticulum membranes of eukaryotes. In mammalian cells, signal-sequences are recognized by the 54K protein (M(r) 54,000) of the signal recognition particle (SRP) which is believed to hold ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/359741a0

    authors: Luirink J,High S,Wood H,Giner A,Tollervey D,Dobberstein B

    更新日期:1992-10-22 00:00:00

  • Energetics of running: a new perspective.

    abstract::The amount of energy used to run a mile is nearly the same whether it is run at top speed or at a leisurely pace (although it is used more rapidly at the higher speed). This puzzling independence of energy cost and speed is found generally among running animals, although, on a per gram basis, cost is much higher for s...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/346265a0

    authors: Kram R,Taylor CR

    更新日期:1990-07-19 00:00:00

  • A trans-synaptic nanocolumn aligns neurotransmitter release to receptors.

    abstract::Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresp...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature19058

    authors: Tang AH,Chen H,Li TP,Metzbower SR,MacGillavry HD,Blanpied TA

    更新日期:2016-08-11 00:00:00

  • Molecular modifiers reveal a mechanism of pathological crystal growth inhibition.

    abstract::Crystalline materials are crucial to the function of living organisms, in the shells of molluscs, the matrix of bone, the teeth of sea urchins, and the exoskeletons of coccoliths. However, pathological biomineralization can be an undesirable crystallization process associated with human diseases. The crystal growth of...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature19062

    authors: Chung J,Granja I,Taylor MG,Mpourmpakis G,Asplin JR,Rimer JD

    更新日期:2016-08-25 00:00:00

  • X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis.

    abstract::Non-ribosomal peptide synthetase (NRPS) mega-enzyme complexes are modular assembly lines that are involved in the biosynthesis of numerous peptide metabolites independently of the ribosome. The multiple interactions between catalytic domains within the NRPS machinery are further complemented by additional interactions...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature14141

    authors: Haslinger K,Peschke M,Brieke C,Maximowitsch E,Cryle MJ

    更新日期:2015-05-07 00:00:00

  • Fertility after intact ovary transplantation.

    abstract::Transplantation surgery, which is limited by the supply and short-term viability of fresh donor organs, would be revolutionized if these could survive freezing, but early claims of cryopreservation were never realized. Here we describe the successful transplantation in rats of ovaries, fallopian tubes and the upper se...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/415385a

    authors: Wang X,Chen H,Yin H,Kim SS,Lin Tan S,Gosden RG

    更新日期:2002-01-24 00:00:00

  • The nature and origin of interstellar diamond.

    abstract::Microscopic diamond was recently discovered in oxidized acid residues from several carbonaceous chondrite meteorites (for example, the C delta component of the Allende meteorite). Some of the reported properties of C delta seem in conflict with those expected of diamond. Here we present high spatial resolution analy...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/332611a0

    authors: Blake DF,Freund F,Krishnan KF,Echer CJ,Shipp R,Bunch TE,Tielens AG,Lipari RJ,Hetherington CJ,Chang S

    更新日期:1988-04-14 00:00:00

  • Two independent and primitive envelopes of the bilobate nucleus of comet 67P.

    abstract::The factors shaping cometary nuclei are still largely unknown, but could be the result of concurrent effects of evolutionary and primordial processes. The peculiar bilobed shape of comet 67P/Churyumov-Gerasimenko may be the result of the fusion of two objects that were once separate or the result of a localized excava...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature15511

    authors: Massironi M,Simioni E,Marzari F,Cremonese G,Giacomini L,Pajola M,Jorda L,Naletto G,Lowry S,El-Maarry MR,Preusker F,Scholten F,Sierks H,Barbieri C,Lamy P,Rodrigo R,Koschny D,Rickman H,Keller HU,A'Hearn MF,Agarwal J

    更新日期:2015-10-15 00:00:00

  • Production of dimethylfuran for liquid fuels from biomass-derived carbohydrates.

    abstract::Diminishing fossil fuel reserves and growing concerns about global warming indicate that sustainable sources of energy are needed in the near future. For fuels to be useful in the transportation sector, they must have specific physical properties that allow for efficient distribution, storage and combustion; these pro...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature05923

    authors: Román-Leshkov Y,Barrett CJ,Liu ZY,Dumesic JA

    更新日期:2007-06-21 00:00:00

  • Detection of ozone on Saturn's satellites Rhea and Dione.

    abstract::The satellites Rhea and Dione orbit within the magnetosphere of Saturn, where they are exposed to particle irradiation from trapped ions. A similar situation applies to the galilean moons Europa, Ganymede and Callisto, which reside within Jupiter's radiation belts. All of these satellites have surfaces rich in water i...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/40348

    authors: Noll KS,Roush TL,Cruikshank DP,Johnson RE,Pendleton YJ

    更新日期:1997-07-03 00:00:00

  • Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.

    abstract::Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially ex...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature21379

    authors: Pan Y,Tian T,Park CO,Lofftus SY,Mei S,Liu X,Luo C,O'Malley JT,Gehad A,Teague JE,Divito SJ,Fuhlbrigge R,Puigserver P,Krueger JG,Hotamisligil GS,Clark RA,Kupper TS

    更新日期:2017-03-09 00:00:00

  • Ecosystem stability and compensatory effects in the Inner Mongolia grassland.

    abstract::Numerous studies have suggested that biodiversity reduces variability in ecosystem productivity through compensatory effects; that is, a species increases in its abundance in response to the reduction of another in a fluctuating environment. But this view has been challenged on several grounds. Because most studies ha...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature02850

    authors: Bai Y,Han X,Wu J,Chen Z,Li L

    更新日期:2004-09-09 00:00:00

  • Electric currents couple spatially separated biogeochemical processes in marine sediment.

    abstract::Some bacteria are capable of extracellular electron transfer, thereby enabling them to use electron acceptors and donors without direct cell contact. Beyond the micrometre scale, however, no firm evidence has previously existed that spatially segregated biogeochemical processes can be coupled by electric currents in n...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature08790

    authors: Nielsen LP,Risgaard-Petersen N,Fossing H,Christensen PB,Sayama M

    更新日期:2010-02-25 00:00:00

  • Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.

    abstract::Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 ...

    journal_title:Nature

    pub_type: 信件

    doi:10.1038/nature04788

    authors: Park J,Lee SB,Lee S,Kim Y,Song S,Kim S,Bae E,Kim J,Shong M,Kim JM,Chung J

    更新日期:2006-06-29 00:00:00

  • Antibacterial agents specifically inhibiting lipopolysaccharide synthesis.

    abstract::The spread of antibiotic resistance in Gram-negative bacteria has sustained a continuing search for new agents with antibacterial activity against this important class of bacterial pathogen. Because the biosynthesis of lipopolysaccharide (LPS) is unique to Gram-negative bacteria and required by them for growth and vir...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/329162a0

    authors: Goldman R,Kohlbrenner W,Lartey P,Pernet A

    更新日期:1987-09-10 00:00:00

  • The hydrodynamics of water strider locomotion.

    abstract::Water striders Gerridae are insects of characteristic length 1 cm and weight 10 dynes that reside on the surface of ponds, rivers, and the open ocean. Their weight is supported by the surface tension force generated by curvature of the free surface, and they propel themselves by driving their central pair of hydrophob...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature01793

    authors: Hu DL,Chan B,Bush JW

    更新日期:2003-08-07 00:00:00

  • An extended upper atmosphere around the extrasolar planet HD209458b.

    abstract::The planet in the system HD209458 is the first one for which repeated transits across the stellar disk have been observed. Together with radial velocity measurements, this has led to a determination of the planet's radius and mass, confirming it to be a gas giant. But despite numerous searches for an atmospheric signa...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature01448

    authors: Vidal-Madjar A,Des Etangs AL,Désert JM,Ballester GE,Ferlet R,Hébrard G,Mayor M

    更新日期:2003-03-13 00:00:00