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
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Czech description
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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
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Result continuities
Project
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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
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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