The local production of 1,25(OH)2D3 promotes osteoblast and osteocyte maturation
Abstract
Maintenance of an adequate vitamin D status, as indicated by the level of circulating 25-hydroxyvitamin D (25(OH)D), is associated with higher bone mass and decreased risk of fracture. However, the molecular actions of vitamin D hormone (1,25(OH)2D3) in bone are complex, and include stimulation of osteoclastogenesis via RANK-ligand up-regulation, as well as the inhibition of mineralisation. We hypothesise that these divergent data may be reconciled by autocrine actions of 1,25(OH)2D3 which effect skeletal maintenance, as opposed to endocrine 1,25(OH)2D3 which acts to maintain serum calcium homeostasis. We have previously described local metabolism of 1,25(OH)2D3 within osteoblasts, with effects on gene expression and cell function. The aim of the current study was to investigate potential autocrine actions of 1,25(OH)2D3 within cells that exhibit osteocyte-like properties. Late osteoblastic MLO-A5 cells were cultured in the presence of 25(OH)D for 9 days with gene expression analysed pre- and post-mineralisation. Gene expression analysis revealed maturation within this time frame to an osteocyte-like stage, evidenced by increased Dmp1 and Phex mRNA expression. Expression of Cyp27b1 in 25(OH)D treated MLO-A5 cells was associated with elevated media levels of 1,25(OH)2D3 (p<0.05), induction of Cyp24a1 (p<0.001) and elevated ratios of Opg:Rankl mRNA (p<0.01). Chronic 25(OH)D exposure also increased osteocalcin mRNA in MLO-A5 cells, which contrasted with the dose-dependent inhibition of osteocalcin mRNA observed with acute treatment in MLO-Y4 cells (p<0.01). Treatment of MLO-Y4 cells with 25(OH)D also inhibited Phex mRNA expression (p<0.05), whilst Enpp1 gene expression was induced (p<0.01). Overall, the current study demonstrates that osteocyte-like cells convert physiological levels of 25(OH)D to 1,25(OH)2D3, with changes in gene expression that are consistent with increased osteocyte maturation. Although the physiological role of local metabolism of 1,25(OH)2D3 within osteocytes requires further investigation, the abundance and diverse functions of this cell type within bone underscore its potential importance. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
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In addition to its systemic effects, 1,25(OH)2D3 binds to VDR in osteocytes in an autocrine manner, and as they mature, osteocytes acquire the capacity to convert physiological levels of 25(OH)D to 1,25(OH)2D3.
“In addition to its systemic effects, 1,25(OH)2D3 binds to VDR in osteocytes in an autocrine manner, and as they mature, osteocytes acquire the capacity to convert physiological levels of 25(OH)D to 1,25(OH)2D3.99”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [99]
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- Authors
- Turner, A. G., Hanrath, M. A., Morris, H. A., Atkins, G. J., & Anderson, P. H.
- Affiliations
- University of South Australia (AU)
- Utrecht University (NL)
- The University of Adelaide (AU)
- Corresponding author
- Turner, Andrew G.
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 144
- Pages
- 114-118
- ISSN
- 0960-0760 (ISSN-L)
- OpenAlex
- W1988986529
- Cited by
- 57
- References
- 22
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 8 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 10 · 2014: 2
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D, autocrine signaling, osteogenic differentiation, MLO-Y4 cells, CYP27B1, CYP24A1, PHEX, ENPP1, DMP1, osteocalcin, RANKL/OPG ratio, bone mineralization, osteoclastogenesis, vitamin D receptor
- MeSH terms
- Animals, Calcitriol, Cell Differentiation, Humans, Osteoblasts, Osteocytes, Vitamins
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