title: Statin treatment rescues FGFR3 skeletal dysplasia phenotypes.
abstract: Gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3) result in skeletal dysplasias, such as thanatophoric dysplasia and achondroplasia (ACH). The lack of disease models using human cells has hampered the identification of a clinically effective treatment for these diseases. Here we show that statin treatment can rescue patient-specific induced pluripotent stem cell (iPSC) models and a mouse model of FGFR3 skeletal dysplasia. We converted fibroblasts from thanatophoric dysplasia type I (TD1) and ACH patients into iPSCs. The chondrogenic differentiation of TD1 iPSCs and ACH iPSCs resulted in the formation of degraded cartilage. We found that statins could correct the degraded cartilage in both chondrogenically differentiated TD1 and ACH iPSCs. Treatment of ACH model mice with statin led to a significant recovery of bone growth. These results suggest that statins could represent a medical treatment for infants and children with TD1 and ACH.
authors.affiliation: Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Morioka
authors.affiliation: Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kishi
authors.affiliation: 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Yahara
authors.affiliation: Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.affiliation: Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Obstetrics and Gynecology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Sawai
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrated Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Tsumaki
mesh_terms: D000130:Achondroplasia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001846:Bone Development / Q000187:drug effects; D002356:Cartilage / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000473:pathology; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000172:deficiency* / Q000235:genetics*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013796:Thanatophoric Dysplasia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D008148:Lovastatin; D051498:Receptor, Fibroblast Growth Factor, Type 3