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 .

Diseases
Validation

Diseases presenting "growth factor receptor" symptom

achondroplasia

aromatase deficiency

cholangiocarcinoma

dedifferentiated liposarcoma

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

kallmann syndrome

lymphangioleiomyomatosis

oral submucous fibrosis

proteus syndrome

severe combined immunodeficiency

wiskott-aldrich syndrome

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