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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 
 Journal of Clinical Endocrinology & Metabolism, Vol.101(10) : 3700-3708, 2016 
Journal Title
 Journal of Clinical Endocrinology & Metabolism 
Issue Date
Animals ; Bone Density/drug effects* ; Cell Culture Techniques ; Female ; Mice ; Mice, Inbred C57BL ; Ovariectomy ; Parathyroid Hormone/analysis ; Parathyroid Hormone/genetics ; Parathyroid Hormone/pharmacology* ; Signal Transduction/drug effects*
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
강명모(Kang, Myengmo)
신동민(Shin, Dong Min) ORCID logo https://orcid.org/0000-0001-6042-0435
임승길(Lim, Sung Kil)
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