ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F17%3A00483011" target="_blank" >RIV/67985904:_____/17:00483011 - isvavai.cz</a>
Alternative codes found
RIV/00216224:14110/17:00095264 RIV/00159816:_____/17:00067152
Result on the web
<a href="http://dx.doi.org/10.1016/j.bone.2017.08.016" target="_blank" >http://dx.doi.org/10.1016/j.bone.2017.08.016</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bone.2017.08.016" target="_blank" >10.1016/j.bone.2017.08.016</a>
Alternative languages
Result language
angličtina
Original language name
ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3
Original language description
Tyrosine kinase inhibitors are being developed for therapy of malignancies caused by oncogenic FGFR signaling but little is known about their effect in congenital chondrodysplasias or craniosynostoses that associate with activating FGFR mutations. Here, we investigated the effects of novel FGFR inhibitor, ARQ 087, in experimental models of aberrant FGFR3 signaling in cartilage. In cultured chondrocytes, ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation, i.e. inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. In ex vivo tibia organ cultures, ARQ087 restored normal growth plate architecture and eliminated the suppressing FGFR3 effect on chondrocyte hypertrophic differentiation, suggesting that it targets the FGFR3 pathway specifically, i.e. without interference with other pro-growth pathways. Moreover, ARQ 087 inhibited activity of FGFR1 and FGFR2 mutants associated with Pfeiffer, Apert and Beare-Stevenson craniosynostoses, and rescued FGFR-driven excessive osteogenic differentiation in mouse mesenchymal micromass cultures or in ex vivo calvarial organ cultures. Our data warrant further development of ARQ 087 for clinical use in skeletal disorders caused by activating FGFR mutations.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10605 - Developmental biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Bone
ISSN
8756-3282
e-ISSN
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Volume of the periodical
105
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
10
Pages from-to
57-66
UT code for WoS article
000413994500008
EID of the result in the Scopus database
2-s2.0-85028050791