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Achondroplasia (ACH) is one of the most common short-limbed skeletal dysplasias caused by gain-of-function mutations in the fibroblast growth factor receptors 3 (FGFR3) gene. Distraction osteogenesis (DO) is a treatment option for short stature in ACH in some countries. Although the patients with ACH usually show faster healing in DO, details of the newly formed bone have not been examined. We have developed a mouse model of DO and analyzed new bone regenerates of the transgenic mice with ACH (Fgfr3ach mice) histologically and morphologically. We established two kinds of DO protocols, the short-DO consisted of 5days of latency period followed by 5days of distraction with a rate of 0.4mm per 24h, and the long-DO consisted of the same latency period followed by 7days of distraction with a rate of 0.3mm per 12h. The callus formation was evaluated radiologically by bone fill score and quantified by micro-CT scan in both protocols. The histomorphometric analysis was performed in the short-DO protocol by various stainings, including Villanueva Goldner, Safranin-O/Fast green, tartrate-resistant acid phosphatase, and type X collagen. Bone fill scores were significantly higher in Fgfr3ach mice than in wild-type mice in both protocols. The individual bone parameters, including bone volume and bone volume/tissue volume, were also significantly higher in Fgfr3ach mice than in wild-type mice in both protocols. The numbers of osteoblasts, as well as osteoclasts, around the trabecular bone were increased in Fgfr3ach mice. Cartilaginous tissues of the distraction region rapidly disappeared in Fgfr3ach mice compared to wild-type mice during the consolidation phase. Similarly, type X collagen-positive cells were markedly decreased in Fgfr3ach mice during the same period. Fgfr3ach mice exhibited accelerated bone regeneration after DO. Accelerated endochondral ossification could contribute to faster healing in Fgfr3ach mice.

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3). No effective FGFR3-targeted therapies for ACH are currently available. By drug repositioning strategies, we identified that meclozine, which has been used as an anti-motion-sickness, suppressed FGFR3 signaling in chondrocytes and rescued short-limbed phenotype in ACH mouse model. Here, we conducted various pharmacological tests for future clinical application in ACH. Pharmacokinetic analyses demonstrated that peak drug concentration (Cmax) and area under the concentration-time curve (AUC) of 2 mg/kg of meclozine to mice was lower than that of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. Pharmacokinetic simulation studies showed that repeated dose of 2 mg/kg of meclozine showed no accumulation effects. Short stature phenotype in the transgenic mice was significantly rescued by twice-daily oral administration of 2 mg/kg/day of meclozine. In addition to stimulation of longitudinal bone growth, bone volume and metaphyseal trabecular bone quality were improved by meclozine treatment. We confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined.

The purpose of this study is to investigate the morphometric changes of the subchondral bone during the development of osteoarthritis (OA) in transgenic mice with achondroplasia (Fgfr3ach ) carrying a heterozygous gain-of-function mutation in Fgfr3. Two OA models (spontaneously developed with age: The aging model, and surgically induced by destabilization of the medial meniscus: The DMM model) were established. Articular cartilage, epiphysis, and metaphysis of the knee joint were histologically and morphometrically compared between wild-type mice, and Fgfr3ach mice in both OA models. Articular cartilage degeneration was scored according to the Osteoarthritis Research Society International (OARSI) scoring system. Several morphometric parameters including bone mineral density (BMD), bone volume/tissue volume (BV/TV), trabecular bone thickness (Tb.Th), and subchondral bone thickness in the medial tibial plateau (MTP) (Sb.Th med) were quantified by micro-computed tomography (CT). In the aging model, although there were no significant differences in the OARSI score between wild-type mice and Fgfr3ach mice, Sb.Th med and Tb.Th in the epiphysis significantly increased in wild-type mice. In the DMM model, the OARSI score of the medial compartment was significantly lower in Fgfr3ach mice than in wild-type mice. BMD, BV/TV, and Tb.Th in the epiphysis increased in wild-type mice and unchanged in Fgfr3ach mice, and the Sb.Th med was significantly larger in wild-type mice after surgery. Subchondral sclerosis, which preceded the cartilage degeneration, was inhibited in Fgfr3ach mice. Activated FGFR3 signaling prevented sclerotic changes of the subchondral bone and subsequent cartilage degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:300-308, 2018.

The purpose of this study is to investigate the morphometric changes of the subchondral bone during the development of osteoarthritis (OA) in transgenic mice with achondroplasia (Fgfr3

OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3ach mice than in wild-type mice (p < 0.005). There were no bony bridges in the spheno-occipital and anterior intraoccipital synchondroses in wild-type mice, while some of the synchondroses prematurely closed in untreated Fgfr3ach mice at PD 4.5. The average bony bridge score in the cranial base was 7.053 ± 1.393 in untreated Fgfr3ach mice and 6.125 ± 2.029 in meclozine-treated Fgfr3ach mice. The scores were not statistically significant between mice with and those without meclozine treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 ± 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 ± 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature closure of synchondroses in some Fgfr3ach mice, but the effect on preventing bony bridge formation was not significant, probably due to low placental transmission of the drug. Meclozine is likely to exhibit a marginal effect on premature closure of synchondroses at the cranial base in ACH.