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Cited by 254Bone Metabolism and DiseasesVitamin D Research StudiesBone health and osteoporosis research

Anabolic Effects of 1,25-Dihydroxyvitamin D3 on Osteoblasts Are Enhanced by Vascular Endothelial Growth Factor Produced by Osteoblasts and by Growth Factors Produced by Endothelial Cells*

Wang, Da Shen, Miura, Masakazu, Demura, Hiroshi, Sato, Kanji·1997·Endocrinology
DOI 10.1210/endo.138.7.5275
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Abstract

Human osteoblast-like cells (HOB) produce vascular endothelial growth factor (VEGF), the steady state level of which is stimulated by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. As osteoblasts and endothelial cells are proximally located in skeletal tissue, we investigated the anabolic effects of 1,25-(OH)2D3 and VEGF on HOB cocultured with endothelial cells. When HOB with high alkaline phosphatase (Al-P) activity and human umbilical vein endothelial cells (HUVEC) with little activity were cultured together, Al-P activity increased, accompanied by an increase in cell number. When HOB and HUVEC were cultured separately, 1,25-(OH)2D3 did not directly stimulate [3H]thymidine incorporation into HUVEC, but stimulated it in the presence of HOB. VEGF did not directly stimulate the Al-P activity of HOB but stimulated it in the presence of HUVEC. The conditioned medium of HOB stimulated the proliferation of HUVEC, and this was partially blocked by anti-VEGF antibody. Conversely, the conditioned medium of HUVEC increased Al-P activity and [3H]thymidine incorporation into HOB, and this was partially blocked by antiinsulin-like growth factor I antibody and BQ-123, a specific antagonist of the endothelin-1 (ET-1) receptor. 1,25-(OH)2D3 stimulated the release of VEGF and ET-1 from HOB and HUVEC, respectively. Furthermore, the 1,25-(OH)2D3-induced release of VEGF was enhanced in HOB cocultured with HUVEC. A quantitative reverse transcription-PCR study revealed that genes for VEGF receptors (Flt-1 and KDR) were expressed in HUVEC, but not in HOB, and that 1,25-(OH)2D3 increased the levels of expression of VEGF receptor genes in endothelial cells only when cocultured with HOB. In summary, we demonstrated that 1,25-(OH)2D3 exerts an anabolic effect on osteoblasts by enhancing their production of VEGF, which stimulates its receptors on endothelial cells, followed by increased production of osteotropic growth factors, such as insulin-like growth factor I and ET-1. These in vitro findings suggest that the VEGF/VEGF receptor system may be involved in both bone formation and bone remodeling in vivo.

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Authors
Wang, D. S., Miura, M., Demura, H., & Sato, K.
Affiliations
  • Tokyo Women's Medical University (JP)
  • Mitsubishi Kagaku BCL (M.M.), Itabashi-ku, Tokyo, Japan
Corresponding author
Sato, Kanji
ORCID
Miura, Masakazu
Venue
Endocrinology
Publisher
The Endocrine Society
Published
1997-07-01
Volume
138
Issue
7
Pages
2953-2962
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endo.138.7.5275
OpenAlex
W2019113771
Cited by
254
References
58
Citations by year
2025: 3 · 2024: 1 · 2023: 9 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 12 · 2018: 9 · 2017: 4 · 2016: 9 · 2015: 8 · 2014: 13 · 2013: 16 · 2012: 10
FWCI
2.02
Type
journal article
Language
en
Open access
closed
Locations
  • Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
1,25-dihydroxyvitamin D3, vascular endothelial growth factor, osteoblasts, endothelial cells, human umbilical vein endothelial cells, endothelin-1, insulin-like growth factor I, VEGF receptors, Flt-1, KDR, alkaline phosphatase activity, bone formation, bone remodeling, endothelial cell proliferation, conditioned medium, BQ-123, anti-VEGF antibody, gene expression
MeSH terms
Alkaline Phosphatase, Calcitriol, Endothelium, Vascular, Humans, Lymphokines, Models, Biological, Osteoblasts, Receptors, Mitogen, Endothelial Growth Factors, Receptors, Growth Factor, Coculture Techniques, Endothelin-1, Endothelin-2, Endothelin-3, Receptor Protein-Tyrosine Kinases, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A

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