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

OBJECTIVE: Statins are widely used drugs for cholesterol lowering, which were recently found to counteract the effects of aberrant fibroblast growth factor receptor (FGFR3) signaling in cell and animal models of FGFR3-related chondrodysplasia. This opened an intriguing therapeutic possibility for human dwarfing conditions caused by gain-of-function mutations in FGFR3, although the mechanism of statin action on FGFR3 remains unclear. Here, we determine the effect of statins on FGFR signaling in chondrocytes. DESIGN: Cultured chondrocyte cell lines, mouse embryonic tibia cultures and limb bud micromasses were treated with FGF2 to activate FGFR signaling. The effects of atorvastatin, fluvastatin, lovastatin and pravastatin on FGFR3 protein stability and on FGFR-mediated chondrocyte growth-arrest, loss of extracellular matrix (ECM), induction of premature senescence and hypertrophic differentiation were evaluated. RESULTS: Statins did not alter the level of FGFR3 protein expression nor produce any effect on FGFR-mediated inhibition of chondrocyte proliferation and hypertrophic differentiation in cultured chondrocyte cell lines, mouse tibia cultures or limb bud micromasses. CONCLUSION: We conclude that statins do not inhibit the FGFR signaling in chondrocytes. Therefore the statin-mediated rescue of FGFR3-related chondrodysplasia, described before, is likely not intrinsic to the growth plate cartilage.

• MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné linie MeSH
• chondrocyty účinky léků   metabolismus   MeSH
• chondrogeneze účinky léků   MeSH
• končetinové pupeny účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši MeSH
• receptor fibroblastových růstových faktorů, typ 3 antagonisté a inhibitory   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• statiny farmakologie   MeSH
• techniky tkáňových kultur MeSH
• tibie účinky léků   embryologie   růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH