Achondroplasia (ACH) is one of the most common skeletal dysplasias with severe short stature caused by gain-of-function mutations in the FGFR3 gene. We previously demonstrated that meclozine, an over-the-counter drug for motion sickness, promoted longitudinal bone growth in transgenic ACH mice by inhibiting FGFR3 signaling. In the present study, we investigated the optimal dose of meclozine for promoting bone growth in ACH mice in order to aim for the clinical application.
The 2 and 20 mg/kg/day of meclozine were administrated to postnatal day 7 of Fgfr3ach mice for 10 days. Body lengths were measured during the administration periods. At the end of the treatment, the mice were subjected to micro-computed tomography (micro-CT) scans for calculating the bone length, bone volume, and the area of foramen magnum. Plasma concentration-time course of meclozine was measured by collecting blood samples from 8-week-old mice given a single oral dose of 2, 6, 20 mg/kg of meclozine.
The 2 mg/kg/day of meclozine significantly increased the total bone volume in Fgfr3ach mice. Body lengths and bone lengths including the cranium, humerus, radius, ulna, femur, tibia, and vertebrae in the 2 mg/kg/day of meclozine-treated Fgfr3ach mice were longer than those in the untreated Fgfr3ach mice. The 20 mg/kg/day of meclozine, however, did not increase body lengths and bone lengths possibly due to the toxicity. On the other hand, foramen magnum area showed no differences between Fgfr3ach mice with and without the 2 and 20 mg/kg/day of meclozine treatment. The plasma concentration-time course of mice after receiving 2 mg/kg of meclozine was almost similar to that of human subjects after receiving 25 mg meclozine oral solution, which has been already used in clinical setting for motion sickness.
Therefore, the continuous dose of meclozine used in clinical settings for motion sickness could improve the short stature in human ACH.