Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia.

[achondroplasia]

Achondroplasia (ACH ) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR 3 encoding the fibroblast growth factor receptor 3 . We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR 3 signaling in ACH . We found that meclozine , an anti-histamine drug that has long been used for motion sickness , facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF 2 -treated rat chondrosarcoma (RCS ) cells . Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS -2 /8 ) cells that were infected with lentivirus expressing constitutively active mutants of FGFR 3 -K 650 E causing thanatophoric dysplasia , FGFR 3 -K 650 M causing SADDAN , and FGFR 3 -G 380 R causing ACH . Similarly , meclozine alleviated abnormally suppressed differentiation of ATDC 5 chondrogenic cells expressing FGFR 3 -K 650 E and -G 380 R in micromass culture . We also confirmed that meclozine alleviates FGF 2 -mediated longitudinal growth inhibition of embryonic tibia in bone explant culture . Interestingly , meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF 2 treatment . Analyses of intracellular FGFR 3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF 2 -treated RCS cells . Similarly , meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK , which suggests that meclozine downregulates the FGFR 3 signaling by possibly attenuating ERK phosphorylation . We used the C-natriuretic peptide (CNP ) as a potent inhibitor of the FGFR 3 signaling throughout our experiments , and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR 3 signaling . We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR 3 -related skeletal dysplasias .

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Diseases presenting "potential therapeutic agent" symptom

achondroplasia

canavan disease

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