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, ARQ 087 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.
- MeSH
- aniliny farmakologie terapeutické užití MeSH
- bezbuněčný systém MeSH
- buněčná diferenciace * účinky léků MeSH
- buněčné kultury MeSH
- chinazoliny farmakologie terapeutické užití MeSH
- chondrocyty účinky léků metabolismus patologie MeSH
- extracelulární matrix účinky léků metabolismus MeSH
- fibroblastový růstový faktor 2 farmakologie MeSH
- končetinové pupeny patologie MeSH
- kraniosynostózy farmakoterapie genetika patologie MeSH
- krysa rodu rattus MeSH
- kur domácí MeSH
- lebka patologie MeSH
- mutace genetika MeSH
- myši MeSH
- orgánové kultury - kultivační techniky MeSH
- proliferace buněk účinky léků MeSH
- receptory fibroblastových růstových faktorů genetika MeSH
- signální transdukce * MeSH
- stárnutí buněk účinky léků MeSH
- tibie účinky léků patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
