Meclozine Promotes Longitudinal Skeletal Growth in Transgenic Mice With Achondroplasia Carrying a Gain-Of-Function Mutation in the FGFR3 Gene

Endocrinology. 2015 Feb;156(2):548-54. doi: 10.1210/en.2014-1914. Epub 2014 Dec 2.

Abstract

Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of meclozine administration in clinical settings, we investigated the effects of meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without meclozine treatment. In Fgfr3(ach) mice, meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, meclozine also increased bone growth in wild-type mice. The plasma concentration of meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of meclozine in a growth period suggests potential clinical feasibility of meclozine for the improvement of short stature in ACH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Achondroplasia / drug therapy*
  • Achondroplasia / genetics
  • Animals
  • Bone Development / drug effects*
  • Female
  • Histamine H1 Antagonists / blood
  • Histamine H1 Antagonists / pharmacology
  • Histamine H1 Antagonists / therapeutic use*
  • In Vitro Techniques
  • Male
  • Meclizine / blood
  • Meclizine / pharmacology
  • Meclizine / therapeutic use*
  • Mice, Transgenic
  • Mutation
  • Random Allocation
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Tibia / growth & development

Substances

  • Histamine H1 Antagonists
  • Meclizine
  • Fgfr3 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 3