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），经皮下注射可缓解侏儒类型的骨骼生长发育障碍。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，发现了重组人甲状旁腺激素的又一功效，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。日前，相关研究论文发表在国际权威杂志《人类分子遗传》上。
第三军医大学发现一种骨质疏松药物可治疗侏儒症
特立帕肽药物功效的研究
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。
特立帕肽(Teriparatide)是目前已上市的唯一促进骨形成的抗骨质疏松含34个氨基酸的多肽药物，用于治疗男性和绝经后女性的骨质疏松症。其含重组人体副甲状腺荷尔蒙片段rhPTH(1-34)，由于刺激成骨作用多于蚀骨作用，因而促进小梁骨与皮质骨表面的新骨生成。不过，副作用是容易导致骨折。
陈林课题组对特立帕肽药物的研究
陈林课题组在国家973计划项目、国家自然科学基金等多项课题的资助下，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。
据陈林介绍，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。
Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia
Yangli Xie, Nan Su, Min Jin, Huabing Qi, Junbao Yang, Can Li, Xiaolan Du, Fengtao Luo, Bo Chen, Yue Shen, Haiyang Huang, Cory J. Xian, Chuxia Deng and Lin Chen
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.
文献链接： Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia
