Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes

Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Activated FGFR3, which is a negative regulator of bone elongation, impairs the growth of long bones and the spinal arch by inhibiting chondrocyte proliferation and differentiation. Most patients with ACH have spinal canal stenosis in addition to short stature. Meclozine has been found to inhibit FGFR3 via drug repurposing. A 10-d treatment with meclozine promoted long-bone growth in a mouse model of ACH (Fgfr3ach mice). This study aimed to evaluate the effects of long-term meclozine administration on promoting bone growth and the spinal canal in Fgfr3ach mice. Meclozine (2 mg/kg/d) was orally administered to Fgfr3ach mice for 5 d per wk from the age of 7 d to 56 d. Meclozine (2 mg/kg/d) significantly reduced the rate of death or paralysis and improved the length of the body, cranium, and long bones in male and female Fgfr3ach mice. Micro-computed tomography analysis revealed that meclozine ameliorated kyphotic deformities and trabecular parameters, including BMD, bone volume/tissue volume, trabecular thickness, and trabecular number at distal femur of Fgfr3ach mice in both sexes. Histological analyses revealed that the hypertrophic zone in the growth plate was restored in Fgfr3ach mice following meclozine treatment, suggesting upregulation of endochondral ossification. Skeletal preparations demonstrated that meclozine restored the spinal canal diameter in Fgfr3ach mice in addition to improving the length of each bone. The 2 mg/kg/d dose of meclozine reduced the rate of spinal paralysis caused by spinal canal stenosis, maintained the growth plate structure, and recovered the bone quality and growth of axial and appendicular skeletons of Fgfr3ach mice in both sexes. Long-term meclozine administration has the potential to ameliorate spinal paralysis and bone growth in patients with ACH. Achondroplasia (ACH) is a rare bone disease characterized by short stature. ACH is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In addition to the short stature, most patients with ACH are suffering from paralysis owing to an abnormal narrowing of spinal canal. A mouse model of ACH shows short stature and half of them are paralyzed related to the spinal deformity until the age of 28 d. We previously demonstrated that meclozine, which has been used as an anti-motion sickness, promoted bone growth by inhibiting FGFR3. In this study, we orally provided meclozine to ACH mice from the age of 7 d to 56 d. We found that the number of paralyzed mice were reduced and their spinal canal were enlarged in addition to promoting bone growth. These results suggest that meclozine has a potential to improve the short stature and spinal paralysis associated with patients with ACH.