Statin treatment rescues FGFR3 skeletal dysplasia phenotypes

• Published in: Nature (London) Vol. 513; no. 7519; pp. 507 - 511
• Main Authors: Yamashita, Akihiro, Morioka, Miho, Kishi, Hiromi, Kimura, Takeshi, Yahara, Yasuhito, Okada, Minoru, Fujita, Kaori, Sawai, Hideaki, Ikegawa, Shiro, Tsumaki, Noriyuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.09.2014; Nature Publishing Group
• Subjects: 13/100; 13/106; 631/532/2064/2158; 64/110; 692/308/3187; Achondroplasia; Achondroplasia - drug therapy; Achondroplasia - genetics; Achondroplasia - pathology; Analysis; Animals; Bone Development - drug effects; Care and treatment; Cartilage - cytology; Cartilage - drug effects; Cartilage - pathology; Cell Differentiation; Chondrocytes - cytology; Chondrocytes - pathology; Diagnosis; Disease; Disease Models, Animal; Female; Fluorobenzenes - administration & dosage; Fluorobenzenes - pharmacology; Fluorobenzenes - therapeutic use; Genotype & phenotype; Humanities and Social Sciences; 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; Kinases; Lovastatin - pharmacology; Lovastatin - therapeutic use; Male; Medical treatment; Mice; Mice, Inbred C57BL; multidisciplinary; Mutation; Patients; Phenotype; Protein kinases; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Radiography; Receptor, Fibroblast Growth Factor, Type 3 - deficiency; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Rosuvastatin Calcium; Science; Statins; Stem cells; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Thanatophoric Dysplasia - drug therapy; Thanatophoric Dysplasia - genetics; Thanatophoric Dysplasia - pathology; Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13775

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. This study reprograms fibroblasts from thanatophoric dysplasia type I (TD1) and achondroplasia (ACH) patients into induced pluripotent stem cells (iPSCs), finding that chondrogenic differentiation results in the formation of degraded cartilage; statin treatment led to significant recovery of bone growth in a mouse model of ACH. Restorative effect of statins on bone growth Some of the most common causes of dwarfism or skeletal dysplasia in humans are the result of gain-of-function mutations in the fibroblast growth factor receptor 3 gene ( FGFR3 ). Noriyuki Tsumaki and colleagues have reprogrammed fibroblasts from patients with two such conditions — thanatophoric dysplasia type 1 (TD1) and achondroplasia (ACH) — to produce induced pluripotent stem cells (iPSCs). Chondrogenic differentiation of TD1 iPSCs resulted in the formation of degraded cartilage. A screen for molecules with the ability to rescue chondrogenically differentiated TD1 iPSCs from the degraded cartilage phenotype identified statins — drugs normally used to reduce blood cholesterol levels — as the most effective. Statins were included as candidate molecules because they have been reported to have anabolic effects on chondrocytes. In addition, statin treatment led to significant recovery of bone growth in a mouse model of ACH. These findings suggest that statins may have potential as a medical treatment for infants and children with TD1 and ACH.