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

Frontiers in Cell and Developmental Biology

Hiroshi Kitoh¹  Shiro Imagama³  Yasuyuki Hosono⁴  Toshinari Ito⁵  Toyofumi Fengshi Chen-Yoshikawa⁵  Yuki Matsuura⁶  Chieko Takashima⁶  Hiromichi Ebi⁶  Genta Takemoto⁷  Takaaki Okamoto⁷  Masaki Matsushita⁷  Kinji Ohno⁷ 

[1] Department of Comprehensive Pediatric Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan;Department of Orthopaedic Surgery, Aichi Children’s Health and Medical Center, Obu, Japan;Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan;Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan;Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan;Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan;Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan;

关键词: FGFR3;    achondroplasia;    meclozine;    zebrafish;    bone;   

DOI  :  10.3389/fcell.2021.694018

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown