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Title: 1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion

Abstract

Sclerostin, the SOST gene product, is a negative regulator of bone formation and a positive regulator of bone resorption. Here, in this study, treatment of human primary osteoblasts, including cells differentiated to an osteocyte-like stage, with 1α,25-dihydroxyvitaminD3 (1,25D) resulted in the dose-dependent increased expression of SOST mRNA. A similar effect was observed in human trabecular bone samples cultured ex vivo, and in osteocyte-like cultures of differentiated SAOS2 cells. Treatment of SAOS2 cells with 1,25D resulted in the production and secretion of sclerostin protein. In silico analysis of the human SOST gene revealed a single putative DR3-type vitamin D response element (VDRE) at position -6216 bp upstream of the transcription start site (TSS). This sequence was confirmed to have strong VDRE activity by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). Sequence substitution in the VDR/RXR half-sites abolished VDRE reporter activity and binding of nuclear proteins. A 6.3 kb fragment of the human proximal SOST promoter demonstrated responsiveness to 1,25D. The addition of the evolutionary conserved region 5 (ECR5), a known bone specific enhancer region, ahead of the 6.3 kb fragment increased basal promoter activity but did not increase 1,25D responsiveness. Site-specific mutagenesis abolished the responsiveness of the 6.3 kbmore » promoter to 1,25D. We conclude that 1,25D is a direct regulator of human SOST gene and sclerostin protein expression, extending the pathways of control of sclerostin expression. At least some of this responsiveness is mediated by the identified classical VDRE however the nature of the transcriptional regulation by 1,25D warrants further investigation.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [2];  [1];  [3];  [1];  [1]
  1. Univ. of Adelaide, SA (Australia)
  2. Univ. of South Australia, Adelaide, SA (Australia)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate; Univ. of California, Merced, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); National Health and Medical Research Council of Australia (NHMRC); National Institutes of Health (NIH)
OSTI Identifier:
1891707
Alternate Identifier(s):
OSTI ID: 1249889
Report Number(s):
LLNL-JRNL-837178
Journal ID: ISSN 0303-7207; 1056922
Grant/Contract Number:  
AC52-07NA27344; ID565372; DK075730
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Molecular and Cellular Endocrinology
Additional Journal Information:
Journal Volume: 413; Journal ID: ISSN 0303-7207
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biological sciences; medical sciences; vitamin D; vitamin D response element; SOST; sclerostin; osteocyte; gene regulation; promoter

Citation Formats

Wijenayaka, Asiri R., Yang, Dongqing, Prideaux, Matthew, Ito, Nobuaki, Kogawa, Masakazu, Anderson, Paul H., Morris, Howard A., Solomon, Lucian B., Loots, Gabriela G., Findlay, David M., and Atkins, Gerald J. 1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion. United States: N. p., 2015. Web. doi:10.1016/j.mce.2015.06.021.
Wijenayaka, Asiri R., Yang, Dongqing, Prideaux, Matthew, Ito, Nobuaki, Kogawa, Masakazu, Anderson, Paul H., Morris, Howard A., Solomon, Lucian B., Loots, Gabriela G., Findlay, David M., & Atkins, Gerald J. 1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion. United States. https://doi.org/10.1016/j.mce.2015.06.021
Wijenayaka, Asiri R., Yang, Dongqing, Prideaux, Matthew, Ito, Nobuaki, Kogawa, Masakazu, Anderson, Paul H., Morris, Howard A., Solomon, Lucian B., Loots, Gabriela G., Findlay, David M., and Atkins, Gerald J. 2015. "1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion". United States. https://doi.org/10.1016/j.mce.2015.06.021. https://www.osti.gov/servlets/purl/1891707.
@article{osti_1891707,
title = {1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion},
author = {Wijenayaka, Asiri R. and Yang, Dongqing and Prideaux, Matthew and Ito, Nobuaki and Kogawa, Masakazu and Anderson, Paul H. and Morris, Howard A. and Solomon, Lucian B. and Loots, Gabriela G. and Findlay, David M. and Atkins, Gerald J.},
abstractNote = {Sclerostin, the SOST gene product, is a negative regulator of bone formation and a positive regulator of bone resorption. Here, in this study, treatment of human primary osteoblasts, including cells differentiated to an osteocyte-like stage, with 1α,25-dihydroxyvitaminD3 (1,25D) resulted in the dose-dependent increased expression of SOST mRNA. A similar effect was observed in human trabecular bone samples cultured ex vivo, and in osteocyte-like cultures of differentiated SAOS2 cells. Treatment of SAOS2 cells with 1,25D resulted in the production and secretion of sclerostin protein. In silico analysis of the human SOST gene revealed a single putative DR3-type vitamin D response element (VDRE) at position -6216 bp upstream of the transcription start site (TSS). This sequence was confirmed to have strong VDRE activity by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). Sequence substitution in the VDR/RXR half-sites abolished VDRE reporter activity and binding of nuclear proteins. A 6.3 kb fragment of the human proximal SOST promoter demonstrated responsiveness to 1,25D. The addition of the evolutionary conserved region 5 (ECR5), a known bone specific enhancer region, ahead of the 6.3 kb fragment increased basal promoter activity but did not increase 1,25D responsiveness. Site-specific mutagenesis abolished the responsiveness of the 6.3 kb promoter to 1,25D. We conclude that 1,25D is a direct regulator of human SOST gene and sclerostin protein expression, extending the pathways of control of sclerostin expression. At least some of this responsiveness is mediated by the identified classical VDRE however the nature of the transcriptional regulation by 1,25D warrants further investigation.},
doi = {10.1016/j.mce.2015.06.021},
url = {https://www.osti.gov/biblio/1891707}, journal = {Molecular and Cellular Endocrinology},
issn = {0303-7207},
number = ,
volume = 413,
place = {United States},
year = {Tue Jun 23 00:00:00 EDT 2015},
month = {Tue Jun 23 00:00:00 EDT 2015}
}

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Works referenced in this record:

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  • Menon, Viviane Barcellos; Moysés, Rosa Maria Affonso; Gomes, Samirah Abreu
  • Clinical Journal of the American Society of Nephrology, Vol. 9, Issue 7
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Works referencing / citing this record:

Vitamin D–regulated osteocytic sclerostin and BMP2 modulate uremic extraskeletal calcification
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DObesity: Relationship between vitamin D deficiency, obesity and sclerostin as a novel biomarker of bone metabolism
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Sclerostin and chronic kidney disease
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Role of the Wnt/β-Catenin Pathway in Renal Osteodystrophy
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Role of the Wnt/β-Catenin Pathway in Renal Osteodystrophy
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1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression
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