25-Hydroxyvitamin D3 induces osteogenic differentiation of human mesenchymal stem cells

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Abstract

25-Hydroxyvitamin D ₃ [25(OH)D ₃] has recently been found to be an active hormone. Its biological actions are demonstrated in various cell types. 25(OH)D ₃ deficiency results in failure in bone formation and skeletal deformation. Here, we investigated the effect of 25(OH)D ₃ on osteogenic differentiation of human mesenchymal stem cells (hMSCs). We also studied the effect of 1α,25-dihydroxyvitamin D ₃ [1α,25-(OH) ₂D ₃], a metabolite of 25(OH)D ₃. One of the vitamin D responsive genes, 25(OH)D ₃-24-hydroxylase (cytochrome P450 family 24 subfamily A member 1) mRNA expression is up-regulated by 25(OH)D ₃ at 250–500 nM and by 1α,25-(OH) ₂D ₃ at 1–10 nM. 25(OH)D ₃ and 1α,25-(OH) ₂D ₃ at a time-dependent manner alter cell morphology towards osteoblast-associated characteristics. The osteogenic markers, alkaline phosphatase, secreted phosphoprotein 1 (osteopontin), and bone gamma-carboxyglutamate protein (osteocalcin) are increased by 25(OH)D ₃ and 1α,25-(OH) ₂D ₃ in a dose-dependent manner. Finally, mineralisation is significantly increased by 25(OH)D ₃ but not by 1α,25-(OH) ₂D ₃. Moreover, we found that hMSCs express very low level of 25(OH)D ₃-1α-hydroxylase (cytochrome P450 family 27 subfamily B member 1), and there is no detectable 1α,25-(OH) ₂D ₃ product. Taken together, our findings provide evidence that 25(OH)D ₃ at 250–500 nM can induce osteogenic differentiation and that 25(OH)D ₃ has great potential for cell-based bone tissue engineering.

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Most cited references 46

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Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro.

Neelam Jaiswal, Stephen E. Haynesworth, Arnold I. Caplan … (1997)

Human bone marrow contains a population of cells capable of differentiating along multiple mesenchymal cell lineages. Recently, techniques for the purification and culture-expansion of these human marrow-derived Mesenchymal Stem Cells (MSCs) have been developed. The goals of the current study were to establish a reproducible system for the in vitro osteogenic differentiation of human MSCs, and to characterize the effect of changes in the microenvironment upon the process. MSCs derived from 2nd or 3rd passage were cultured for 16 days in various base media containing 1 to 1000 nM dexamethasone (Dex), 0.01 to 4 mM L-ascorbic acid-2-phosphate (AsAP) or 0.25 mM ascorbic acid, and 1 to 10 mM beta-glycerophosphate (beta GP). Optimal osteogenic differentiation, as determined by osteoblastic morphology, expression of alkaline phosphatase (APase), reactivity with anti-osteogenic cell surface monoclonal antibodies, modulation of osteocalcin mRNA production, and the formation of a mineralized extracellular matrix containing hydroxyapatite was achieved with DMEM base medium plus 100 nM Dex, 0.05 mM AsAP, and 10 mM beta GP. The formation of a continuously interconnected network of APase-positive cells and mineralized matrix supports the characterization of this progenitor population as homogeneous. While higher initial seeding densities did not affect cell number of APase activity, significantly more mineral was deposited in these cultures, suggesting that events which occur early in the differentiation process are linked to end-stage phenotypic expression. Furthermore, cultures allowed to concentrate their soluble products in the media produced more mineralized matrix, thereby implying a role for autocrine or paracrine factors synthesized by human MSCs undergoing osteoblastic lineage progression. This culture system is responsive to subtle manipulations including the basal nutrient medium, dose of physiologic supplements, cell seeding density, and volume of tissue culture medium. Cultured human MSCs provide a useful model for evaluating the multiple factors responsible for the step-wise progression of cells from undifferentiated precursors to secretory osteoblasts, and eventually terminally differentiated osteocytes.

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Risk assessment for vitamin D.

John N. Hathcock, Andrew Shao, Reinhold Vieth … (2007)

The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 microg, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose > or = 250 microg/d (10,000 IU vitamin D3) supports the confident selection of this value as the UL.

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Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men.

T. Chen, S Dowell, Anthony Heaney … (1997)

We determined the quantitative relationships between graded oral dosing with vitamin D3, 25(OH)D3, and 1,25(OH)2D3 for short treatment periods and changes in circulating levels of these substances. The subjects were 116 healthy men (mean age, 28 +/- 4 years, with usual milk consumption of < or = 0.47 l/day and mean serum 25(OH)D of 67 +/- 25 nmol/l). They were distributed among nine open-label treatment groups: vitamin D3 (25, 250 or 1250 micrograms/day for 8 weeks), 25(OH)D3 (10, 20 or 50 micrograms/day for 4 weeks) and 1,25(OH)2D3 (0.5, 1.0 or 1.0 microgram/day for 2 weeks). All treatment occurred between January 3 and April 3. We measured fasting serum, calcium, parathyroid hormone, vitamin D3, 25(OH)D and 1,25(OH)2D immediately before and after treatment. In the three groups treated with vitamin D3, mean values for circulating vitamin D3 increased by 13, 137 and 883 nmol/l and serum 25(OH)D increased by 29, 146 and 643 nmol/l for the three dosage groups, respectively. Treatment with 25(OH)D3 increased circulating 25(OH)D by 40, 76 and 206 nmol/l, respectively. Neither compound changed serum 1,25(OH)2D levels. However, treatment with 1,25(OH)2D3 increased circulating 1,25(OH)2D by 10, 46 and 60 pmol/l, respectively. Slopes calculated from these data allow the following estimates of mean treatment effects for typical dosage units in healthy 70-kg adults: an 8-week course of vitamin D3 at 10 micrograms/day (400 IU/day) would raise serum vitamin D by 9 nmol/l and serum 25(OH)D by 11 nmol/l; a 4-week course of 25(OH)D3 at 20 micrograms/day would raise serum 25(OH)D by 94 nmol/l; and a 2-week course of 1,25(OH)2D3 at 0.5 microgram/day would raise serum 1,25(OH)2D by 17 pmol/l.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 17 February 2017

Publication date Collection: 2017

Volume: 7

Electronic Location Identifier: 42816

Affiliations

[1 ]Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #04-01, 31 Biopolis Way , Singapore 138669, Singapore

[2 ]Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , 00014 Helsinki, Finland

[3 ]School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore

[4 ]Department of Biological Sciences, National University of Singapore , 14 Science Drive 4, Singapore 117543, Singapore

[5 ]Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , MD9 #04-11, 2 Medical Drive, Singapore 117597, Singapore

[6 ]Mechanobiology Institute, National University of Singapore , T-Laboratories, #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore

[7 ]NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, National University of Singapore , #05-01, 28 Medical Drive, Singapore 117576, Singapore

[8 ]Singapore-MIT Alliance for Research and Technology , 1 CREATE Way, #10-01 CREATE Tower, Singapore 138602, Singapore

[9 ]Department of Biological Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States

[10 ]Department of Gastroenterology, Nanfang Hospital, Southern Medical University , No. 1838, North of Guangzhou Dadao, Guangzhou 510515, China

Author notes

[a ] yan-ru.lou@ 123456helsinki.fi

Article

Publisher Item ID: srep42816

DOI: 10.1038/srep42816

PMC ID: 5314335

PubMed ID: 28211493

SO-VID: 7eadd5a5-536a-4365-99ae-88914107943f

License:

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 12 October 2016

Date accepted : 13 January 2017

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