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
Identifikátory výsledku
Kód výsledku v 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>
Nalezeny alternativní kódy
RIV/00216224:14110/17:00095264 RIV/00159816:_____/17:00067152
Výsledek na webu
<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>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
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
Popis výsledku v původním jazyce
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.
Název v anglickém jazyce
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
Popis výsledku anglicky
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.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10605 - Developmental biology
Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2017
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Bone
ISSN
8756-3282
e-ISSN
—
Svazek periodika
105
Číslo periodika v rámci svazku
1
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
10
Strana od-do
57-66
Kód UT WoS článku
000413994500008
EID výsledku v databázi Scopus
2-s2.0-85028050791