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An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia.
Journal of Bone and Mineral Research ( IF 6.2 ) Pub Date : 2019-12-04 , DOI: 10.1002/jbmr.3913
Hiroshi Noda 1 , Jun Guo 1 , Ashok Khatri 1 , Thomas Dean 1 , Monica Reyes 1 , Michael Armanini 1, 2, 3 , Daniel J Brooks 1, 2, 3 , Janaina S Martins 1 , Ernestina Schipani 4 , Mary L Bouxsein 1, 2, 3 , Marie B Demay 1 , John T Potts 1 , Harald Jüppner 1 , Thomas J Gardella 1
Affiliation  

Jansen's metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligand-independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell-based assays, we found that certain N-terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu11 ,dTrp12 ,Trp23 ,Tyr36 ]-PTHrP(7-36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1-H223R allele of JMC in osteoblastic cells via the collagen-1α1 promoter (C1HR mice). We observed that after 2 weeks of twice-daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proof-of-concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.

中文翻译:

PTH 受体的反向激动剂配体可部分修复 Jansen 干骺端软骨发育不良小鼠模型的骨骼缺陷。

Jansen 的干骺端软骨发育不良 (JMC) 是一种罕见的骨骼和矿物质离子生理疾病,由 PTHR1 的激活突变引起。骨骼和肾脏细胞中突变受体的配体非依赖性信号导致骨骼生长异常、骨转换过度以及慢性高钙血症和高磷尿症。临床特征还包括身材矮小、肢体畸形、肾钙质沉着症和肾功能进行性丧失。JMC 没有可用的有效治疗方案。在以前的基于细胞的测定中,我们发现某些 N 末端截短的 PTH 和 PTHrP 拮抗剂肽起反向激动剂的作用,因此可以降低 JMC 的突变体 PTHR1 在体外表现出的高基底 cAMP 信号传导率。在这里,我们探讨了是否有一种这样的反向激动剂配体,[Leu11,dTrp12,Trp23,Tyr36 ]-PTHrP(7-36)NH2 (IA),可在体内有效,从而改善通过胶原蛋白 1α1 启动子在成骨细胞中表达 JMC 的 PTHR1-H223R 等位基因的转基因小鼠中发生的骨骼异常(C1HR 小鼠). 我们观察到,在每天两次注射 2 周后,与载体对照相比,IA 类似物显着改善了 C1HR 小鼠的关键骨骼参数,因为它减少了多余的小梁骨量、骨髓纤维化和血液和尿液中的骨转换标志物。总体发现为针对 JMC 突变体 PTHR1 变体的反向激动剂配体可以在体内产生疗效这一观点提供了概念验证支持。对此类 PTHR1 配体类似物的进一步研究可能有助于为这种使人衰弱的骨骼疾病开辟第一个治疗选择的途径。© 2019 美国骨骼和矿物研究协会。
更新日期:2019-12-05
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