A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia
A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia
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一种新型 FGFR3 结合肽抑制 FGFR3 信号传导并逆转模仿人类致死性发育不良的小鼠的致死表型
DOI：
10.1093/hmg/dds390
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发表时间：
2012-12-15
影响因子：
3.5
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Jin, Min;Yu, Ying;Chen, Lin
成纤维细胞生长因子受体-3 （FGFR3）的功能获得突变可导致几种类型的人类骨骼发育不良综合征，包括软骨发育不全、软骨发育不全和嗜盐性发育不良（TD）。目前，这些骨骼发育不良疾病没有有效的治疗方法。在本研究中，我们以FGFR3为诱饵，随机筛选了一个12肽噬菌体文库，获得23个具有相同氨基酸序列（vsppltlgqls）的阳性克隆，命名为肽P3。该肽对FGFR3的细胞外结构域具有高结合特异性。P3抑制FGFR3及其典型下游分子（细胞外信号调节激酶/丝裂原活化蛋白激酶）的酪氨酸激酶活性。P3还能促进培养的ATDC5软骨细胞的增殖和软骨分化。此外，P3还能减轻模拟人凋亡性II型发育不良（TDII）小鼠骨幼体的骨生长迟缓。最后，P3逆转了TDII小鼠的新生儿死亡率。因此，本研究确定了一种新的FGFR3信号抑制肽，它可能作为治疗FGFR3相关骨骼发育不良的潜在治疗剂。
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.