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

被引：41

作者：

Jin, Min ^{[1
]}

Yu, Ying ^{[2
]}

Qi, Huabing ^{[1
]}

Xie, Yangli ^{[1
]}

Su, Nan ^{[1
]}

Wang, Xiaofeng ^{[1
]}

Tan, Qiaoyan ^{[1
]}

Luo, Fengtao ^{[1
]}

Zhu, Ying ^{[1
]}

Wang, Quan ^{[1
]}

Du, Xiaolan ^{[1
]}

Xian, Cory J. ^{[3
]}

Liu, Peng ^{[1
]}

Huang, Haiyang ^{[1
]}

Shen, Yue ^{[1
]}

Deng, Chu-Xia ^{[4
]}

Chen, Di ^{[5
]}

Chen, Lin ^{[1
]}

机构：

[1] Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Inst Surg Res, Ctr Bone Metab & Repair,Daping Hosp, Chongqing 400042, Peoples R China

[2] Chongqing Univ Technol, Sch Pharm & Bioengn, Chongqing 400050, Peoples R China

[3] Univ S Australia, Sch Pharm & Med Sci, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia

[4] NIDDKD, Genet Dev & Dis Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA

[5] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA

来源：

HUMAN MOLECULAR GENETICS | 2012年 / 21卷 / 26期

基金：

中国国家自然科学基金;

关键词：

GROWTH-FACTOR RECEPTOR-3; ACTIVATING MUTATIONS; MULTIPLE-MYELOMA; BONE-DEVELOPMENT; CHONDROGENIC DIFFERENTIATION; CHONDROCYTE PROLIFERATION; HORMONE TREATMENT; ACHONDROPLASIA; DWARFISM; EXPRESSION;

D O I：

10.1093/hmg/dds390

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5443 / 5455

页数：13

共 63 条

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