A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia.

[achondroplasia]

Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR 3 ) lead to several types of human skeletal dysplasia syndromes including achondroplasia , hypochondroplasia and thanatophoric dysplasia (TD ). Currently , there are no effective treatments for these skeletal dysplasia diseases . In this study , we screened , using FGFR 3 as a bait , a random 12 -peptide phage library and obtained 23 positive clones that share identical amino acid sequences (VSPPLTLGQLLS ), named as peptide P 3 . This peptide had high binding specificity to the extracellular domain of FGFR 3 . P 3 inhibited tyrosine kinase activity of FGFR 3 and its typical downstream molecules , extracellular signal-regulated kinase /mitogen-activated protein kinase . P 3 also promoted proliferation and chondrogenic differentiation of cultured ATDC 5 chondrogenic cells . In addition , P 3 alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII ). Finally , P 3 reversed the neonatal lethality of TDII mice . Thus , this study identifies a novel inhibitory peptide for FGFR 3 signaling , which may serve as a potential therapeutic agent for the treatment of FGFR 3 -related skeletal dysplasia .

Diseases
Validation

Diseases presenting "skeletal dysplasia" symptom

achondroplasia

aromatase deficiency

cohen syndrome

dentinogenesis imperfecta

gm1 gangliosidosis

oligodontia

This symptom has already been validated