第三军医大历时四年 解析上市药物新功能

　　

生物通报道：来自第三军医大学大坪医院野战外科研究所，南澳大利亚大学等处的研究人员发表了题为“Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia”的文章，历时四年，利用基因敲入技术建立的小鼠模型，分析了一种治疗骨质疏松的药物：特里帕肽（重组人甲状旁腺激素1-34，PTH1-34片段），发现这种药物可缓解侏儒类型的骨骼生长发育障碍，相关成果公布在Human Molecular Genetics杂志上。

这项研究由第三军医大学大坪医院野战外科研究所创伤实验室暨骨代谢与修复中心主任陈林教授带领课题组，经过4年基础研究取得的新成果，这将为临床治疗软骨发育不全、致死性软骨发育不全等提供了重要理论依据。

软骨发育不全、尤其是致死性软骨发育不全除手术外，目前尚无有效的治疗方法。虽然生长激素也被用来治疗软骨发育不全，但需要在青春期以前给予生长激素，且长期效果不佳，副作用明显。

在这篇文章中，研究人员利用基因敲入技术建立的模拟上述疾病的小鼠模型，深入研究了软骨发育不全、致死性软骨发育不全的发生机制。实验中发现软骨发育不全模型小鼠生长板软骨细胞增生活性和分化能力降低，伴甲状旁腺激素信号活性降低，而甲状旁腺激素处理可升高甲状旁腺激素信号及降低培养软骨细胞中成纤维生长因子受体3的表达水平与活性。

实验表明，软骨发育不全小鼠注射甲状旁腺激素1-34可降低成纤维生长因子受体3突变对软骨细胞增殖与分化的抑制作用，缓解软骨发育不全的骨骼生长发育障碍，并改善该小鼠成年后的骨量；致死性软骨发育不全小鼠注射甲状旁腺激素1-34后，可使其免于出生后早期死亡。

特里帕肽是被美国食品药品监督局批准的治疗骨质疏松药物，已上市10余年。因此，该发现为软骨发育不全和致死性软骨发育不全的生物治疗提供了新的药物选择。

（生物通：万纹）

原文摘要：

Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia

Achondroplasia (ACH) and thanatophoric dysplasia (TD) are caused by gain-of-function mutations of fibroblast growth factor receptor 3 (FGFR3) and they are the most common forms of dwarfism and lethal dwarfism, respectively. Currently, there are few effective treatments for ACH. For the neonatal lethality of TD patients, no practical effective therapies are available. We here showed that systemic intermittent PTH (1-34) injection can rescue the lethal phenotype of TD type II (TDII) mice and significantly alleviate the retarded skeleton development of ACH mice. PTH-treated ACH mice had longer naso-anal length than ACH control mice, and the bone lengths of humeri and tibiae were rescued to be comparable with those of wild-type control mice. Our study also found that the premature fusion of cranial synchondroses in ACH mice was partially corrected after the PTH (1-34) treatment, suggesting that the PTH treatment may rescue the progressive narrowing of neurocentral synchondroses that cannot be readily corrected by surgery. In addition, we found that the PTH treatment can improve the osteopenia and bone structure of ACH mice. The increased expression of PTHrP and down-regulated FGFR3 level may be responsible for the positive effects of PTH on bone phenotype of ACH and TDII mice.