title: A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia.
abstract: Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR3) 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 FGFR3 as a bait, a random 12-peptide phage library and obtained 23 positive clones that share identical amino acid sequences (VSPPLTLGQLLS), named as peptide P3. This peptide had high binding specificity to the extracellular domain of FGFR3. P3 inhibited tyrosine kinase activity of FGFR3 and its typical downstream molecules, extracellular signal-regulated kinase/mitogen-activated protein kinase. P3 also promoted proliferation and chondrogenic differentiation of cultured ATDC5 chondrogenic cells. In addition, P3 alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII). Finally, P3 reversed the neonatal lethality of TDII mice. Thus, this study identifies a novel inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia.
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Dapital Hospital, Third Military University, Chongqing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Huabing
authors.initials: H
authors.lastname: Qi
authors.forename: Yangli
authors.initials: Y
authors.lastname: Xie
authors.forename: Nan
authors.initials: N
authors.lastname: Su
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.forename: Qiaoyan
authors.initials: Q
authors.lastname: Tan
authors.forename: Fengtao
authors.initials: F
authors.lastname: Luo
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Du
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Haiyang
authors.initials: H
authors.lastname: Huang
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D012886:Skull / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D013796:Thanatophoric Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D019151:Peptide Library; D010455:Peptides; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3