A novel human PTH analog [Cys25]hPTH(1-34) restores bone mass in ovariectomized mice

Chu Hyun Bae, Myeongmo Kang, Clara Yongjoo Park, Bo Mi Park, Dongdong Zhang, Hee Jin Nam, Yu Mi Yang, Dong Min Shin, Je Yong Choi, Sung Kil Lim

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1 Citation (Scopus)


Context: Recently, an arginine-to-cysteine homozygous mutation at position 25 in mature PTH was reported in a Korean patient with hypoparathyroidism. Objective: To clarify whether the high bone mass phenotype observed in this patient was related to the hypoparathyroidism itself or to chronic elevation of mutant PTH. Methods: A series of in vitro and in vivo experiments were performed in MC3T3E1, ROS 17/2.8, and SAOS2 cells treated with human (h)PTH(1-34), Cys25hPTH(1-34), Ala1Cys25hPTH(1-34), and Bpa1Cys25hPTH(1-34). The peptides were then sc delivered to ovariectomized mice as daily single injections. Results: Compared with hPTH(1-34) and Ala1Cys25hPTH(1-34), treatment with Cys25hPTH(1-34) or Bpa1Cys25hPTH(1-34) resulted in decreases in the cAMP response and promoter-cAMP-response element luciferase reporter activity. Although the cAMP response was sustained with hPTH(1-34) in MC3T3E1 cells, such response was not observed with the other mutated peptides. Meanwhile, all PTH analogues exhibited ERK phosphorylation and cytoplasmic Ca signals comparable with hPTH(1-34). On microcomputed tomography analyses, trabecular and cortical bone parameters improved after 6 weeks of respective treatments as follows: hPTH(1-34) (80 μg/kg)-Ala1Cys25hPTH(1-34)(80 μg/kg)-Cys25hPTH(1-34)(80 μg/kg)-Bpa1Cys25hPTH(1-34)(80 μg/kg)-hPTH(1-34) (40 μg/kg). The increment of RANKL to OPG mRNA ratio in the MC3T3E1 cells after 6 hours of treatment of Cys25hPTH(1-34), AL1Cys25hPTH(1-34), and Bpa1Cys25hPTH(1-34) was less than that was obtained after hPTH(1-34) treatment. On bone histomorphometric analysis, AL1Cys25hPTH(1-34) increased the bone formation rate in both trabecular and periosteal bones compared with the control group. Conclusion: The high bone mass phenotype observed in this patient with hypoparathyrodism caused by a Cys mutation at the 25th residue of hPTH(1-84) may have arisen from both direct and indirect effects exerted by the mutant PTH itself on bone.

Original languageEnglish
Pages (from-to)3700-3708
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Issue number10
Publication statusPublished - 2016 Oct

Bibliographical note

Funding Information:
This work was supported by a Brain Korea 21 PLUS grant and by the National Research Foundation of Korea Grant 2014M3A9D5A01073658.

Publisher Copyright:
© 2016 by the Endocrine Society.

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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