Statin treatment rescues FGFR3 skeletal dysplasia phenotypes

Akihiro Yamashita; Miho Morioka; Hiromi Kishi; Takeshi Kimura; Yasuhito Yahara; Minoru Okada; Kaori Fujita; Hideaki Sawai; Shiro Ikegawa; Noriyuki Tsumaki

doi:10.1038/nature13775

Statin treatment rescues FGFR3 skeletal dysplasia phenotypes

Nature. 2014 Sep 25;513(7519):507-11. doi: 10.1038/nature13775. Epub 2014 Sep 17.

Authors

Affiliations

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 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.
³ Department of Obstetrics and Gynecology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
⁴ Laboratory of Bone and Joint Diseases, Center for Integrated Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
⁵ 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.

PMID: 25231866
DOI: 10.1038/nature13775

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Achondroplasia / drug therapy*
Achondroplasia / genetics
Achondroplasia / pathology*
Animals
Bone Development / drug effects
Cartilage / cytology
Cartilage / drug effects
Cartilage / pathology
Cell Differentiation
Chondrocytes / cytology
Chondrocytes / pathology
Disease Models, Animal
Female
Fluorobenzenes / administration & dosage
Fluorobenzenes / pharmacology
Fluorobenzenes / therapeutic use
Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / pathology
Lovastatin / pharmacology
Lovastatin / therapeutic use
Male
Mice
Mice, Inbred C57BL
Phenotype
Pyrimidines / administration & dosage
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Receptor, Fibroblast Growth Factor, Type 3 / deficiency*
Receptor, Fibroblast Growth Factor, Type 3 / genetics*
Rosuvastatin Calcium
Sulfonamides / administration & dosage
Sulfonamides / pharmacology
Sulfonamides / therapeutic use
Thanatophoric Dysplasia / drug therapy*
Thanatophoric Dysplasia / genetics
Thanatophoric Dysplasia / pathology*

Substances

Fluorobenzenes
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pyrimidines
Sulfonamides
Rosuvastatin Calcium
Lovastatin
Receptor, Fibroblast Growth Factor, Type 3

Supplementary concepts

Thanatophoric Dysplasia, Type I