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Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F16%3A10333332" target="_blank" >RIV/00216208:11110/16:10333332 - isvavai.cz</a>

  • Alternative codes found

    RIV/00023728:_____/16:N0000045

  • Result on the web

    <a href="http://dx.doi.org/10.1136/annrheumdis-2015-208420" target="_blank" >http://dx.doi.org/10.1136/annrheumdis-2015-208420</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1136/annrheumdis-2015-208420" target="_blank" >10.1136/annrheumdis-2015-208420</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis

  • Original language description

    Objectives Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice. Methods Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and mu CT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments. Results Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1. Conclusions Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

  • CEP classification

    FE - Other fields of internal medicine

  • OECD FORD branch

Result continuities

  • Project

  • Continuities

    S - Specificky vyzkum na vysokych skolach

Others

  • Publication year

    2016

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Annals of the Rheumatic Diseases

  • ISSN

    0003-4967

  • e-ISSN

  • Volume of the periodical

    75

  • Issue of the periodical within the volume

    11

  • Country of publishing house

    GB - UNITED KINGDOM

  • Number of pages

    8

  • Pages from-to

    2037-2044

  • UT code for WoS article

    000386469300024

  • EID of the result in the Scopus database

    2-s2.0-84958087462