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.
Hum Mol Genet. 2012 Dec 15;21(26):5443-55. doi: 10.1093/hmg/dds390. Epub 2012 Sep 26.
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.
成纤维细胞生长因子受体 3（FGFR3）的功能获得性突变导致几种人类骨骼发育不良综合征，包括软骨发育不全、软骨发育不全和致死性发育不良（TD）。目前，这些骨骼发育不良疾病没有有效的治疗方法。在这项研究中，我们以 FGFR3 为诱饵，筛选了一个随机的 12 肽噬菌体文库，获得了 23 个具有相同氨基酸序列（VSPPLTLGQLLS）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/丝裂原激活蛋白激酶的酪氨酸激酶活性。P3 还促进了培养的 ATDC5 软骨细胞的增殖和软骨分化。此外，P3 缓解了模拟人类致死性发育不良 II 型（TDII）的小鼠骨原基中的骨生长迟缓。最后，P3 逆转了 TDII 小鼠的新生致死性。因此，本研究鉴定了一种用于 FGFR3 信号的新型抑制肽，它可能作为治疗 FGFR3 相关骨骼发育不良的潜在治疗剂。
