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Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin - evidence from in vitro and human studies

Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (position...

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Main Authors: Li, Mei (Author) , Hasan, Ahmed A. (Author) , Chu, Chang (Author) , Hocher, Johann-Georg (Author) , Liu, Yvonne (Author) , Zhang, Xiaoli (Author) , Chen, Xin (Author) , Yard, Benito A. (Author) , Krämer, Bernhard (Author) , Hocher, Berthold (Author)
Format: Article (Journal)
Language:English
Published: 23 February 2024
In: Pflügers Archiv
Year: 2024, Volume: 476, Issue: 6, Pages: 889-899
ISSN:1432-2013
DOI:10.1007/s00424-024-02928-x
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1007/s00424-024-02928-x
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Author Notes:Mei Li, Ahmed A. Hasan, Chang Chu, Johann-Georg Hocher, Yvonne Liu, Xiaoli Zhang, Xin Chen, Benito Yard, Bernhard K. Krämer, Berthold Hocher
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Summary:Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.
Item Description:Gesehen am 06.08.2024
Physical Description:Online Resource
ISSN:1432-2013
DOI:10.1007/s00424-024-02928-x

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