Dataset Information

Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish.

ABSTRACT: Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequencing analysis was performed using murine chondrocytes from FGF2-treated cultured tibiae, which was significantly elongated by meclozine treatment. Gene set enrichment analysis demonstrated that FGF2 significantly increased the enrichment score of mitogen-activated protein kinase (MAPK) family signaling cascades in chondrocytes; however, meclozine reduced this enrichment. Next, we administered meclozine to FGF2-treated larval zebrafish from 8 h post-fertilization (hpf). We observed that FGF2 significantly increased the number of ossified vertebrae in larval zebrafish at 7 days post-fertilization (dpf), while meclozine delayed vertebral ossification in FGF2-induced zebrafish. Meclozine also reversed the FGF2-induced upregulation of ossified craniofacial bone area, including ceratohyal, hyomandibular, and quadrate. The current study provided additional evidence regarding the inhibitory effect of meclozine on the FGF2-induced upregulation of MAPK signaling in chondrocytes and FGF2-induced development of craniofacial and vertebral bones.

SUBMITTER: Takemoto G

PROVIDER: S-EPMC8804316 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish.

Takemoto Genta G Matsushita Masaki M Okamoto Takaaki T Ito Toshinari T Matsuura Yuki Y Takashima Chieko C Chen-Yoshikawa Toyofumi Fengshi TF Ebi Hiromichi H Imagama Shiro S Kitoh Hiroshi H Ohno Kinji K Hosono Yasuyuki Y

Frontiers in cell and developmental biology 20220118

Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequ ...[more]

PMID: 35118060

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Project description:The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix-PAS heterodimeric transcription factor that dimerizes with other basic helix-loop-helix-PAS proteins to mediate biological responses. The function of ARNT2 is poorly understood. Here we provide an initial characterization of the zebrafish arnt2 null (arnt2(-/-)) mutant to identify functions of Arnt2 during development. Arnt2(-/-) mutant zebrafish develop normally until 120 hours postfertilization (hpf ) when morphological changes and functional deficits occur. The C-start escape response initiated by either touch or startle stimuli is absent in the mutants. Brain ventricle size is markedly increased at 120 hpf. Heart ventricles are enlarged, with decreased ventricle wall thickness. A cardiac arrhythmia, characterized by missing beats, is also observed in the mutants. This is associated with bradycardia in arnt2(-/-) larvae. Dilated liver sinusoids merge abnormally to form an extensive, labyrinth-like network of vascular channels. External appearance of arnt2(-/-) larvae at 120 hpf is indistinguishable from wild type except that the swim bladder is not inflated. The arnt2(-/-) mutants are not debilitated when phenotypic effects are first detected at 120 hpf that culminate in mortality, 4 days later around 216 hpf. Gross morphological assessment of the development of forebrain, midbrain, and hindbrain regions, neuromasts and Mauthner neurons, inner ear semicircular canals and otoliths, primary motor neurons, trigeminal ganglia, and trunk skeletal muscles, before or when the arnt2(-/-) phenotype was observed, failed to demonstrate a difference from wild type. The only effect in arnt2(-/-) larvae that occurred before 120 hpf was a decrease in expression of sim1, an Arnt2 dimerization partner, in the hypothalamus and ventral thalamus at 72 hpf. Further research is needed to determine if the primary functions of Arnt2 occur during the larval stage, when the phenotype is observed, or earlier in development.

Dataset Information

Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish.

Publications

Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish.

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