Both ligand and VDR expression levels critically determine the effect of 1α,25-dihydroxyvitamin-D3 on osteoblast differentiation

Dongqing Yang; Paul H Anderson; Asiri R Wijenayaka; Kate R Barratt; Rahma Triliana; Catherine J M Stapledon; Hong Zhou; David M Findlay; Howard A Morris; Gerald J Atkins

doi:10.1016/j.jsbmb.2017.09.005

Both ligand and VDR expression levels critically determine the effect of 1α,25-dihydroxyvitamin-D₃ on osteoblast differentiation

J Steroid Biochem Mol Biol. 2018 Mar:177:83-90. doi: 10.1016/j.jsbmb.2017.09.005. Epub 2017 Sep 6.

Authors

Affiliations

¹ Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia.
² Discipline of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia; Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
³ Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia.
⁴ Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia; Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
⁵ Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
⁶ Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia.
⁷ Discipline of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia; Endocrine Bone Research, Chemical Pathology, SA Pathology, Adelaide, SA, 5000, Australia; Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
⁸ Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia. Electronic address: gerald.atkins@adelaide.edu.au.

PMID: 28887147
DOI: 10.1016/j.jsbmb.2017.09.005

Abstract

Previous studies have shown that 1α,25-dihydroxyvitamin D₃ (1,25D) through vitamin D receptor (VDR) signalling has both catabolic and anabolic effects on osteoblast differentiation. However, the mechanism of these differential effects by 1,25D is not fully understood. In this study, mice with three different genetic backgrounds, representing a normal VDR level (wild-type, WT), VDR over-expression specifically in mature osteoblasts (ObVDR-B6) and global VDR knockout (VDRKO), were utilised to generate primary osteoblast-like cultures to further elucidate the effects of 1,25D on osteoblast differentiation. Our data confirm the importance of VDR in the late stage of osteogenic differentiation and also for the expression of factors critical for osteoblastic support of osteoclast formation. This study also demonstrates the differential effects of a pharmacological level of 1,25D (1nM) on the expression of osteogenic differentiation markers, including Ocn and Sost, depending on the relative level of VDR. Our findings suggest that 1,25D plays an inhibitory role in matrix mineralisation, possibly through the modulation of the tissue non-specific alkaline phosphatase to ectonucleotide pyrophosphatase/phosphodiesterase 1 axis, in a VDR level-dependent manner. We conclude that the relative VDR level and the 1,25D availability to cells, are important co-determinants for whether 1,25D plays a promoting or suppressive role in osteoblast-mediated osteogenic activity.

Keywords: Differentiation; Mineralisation; Osteoblast; VDR; VDR knockout; Vitamin D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Cell Differentiation / drug effects
Cell Line
Gene Expression Regulation / drug effects
Glycoproteins / genetics
Intercellular Signaling Peptides and Proteins
Ligands
Mice, Inbred C57BL
Mice, Transgenic
Osteoblasts / drug effects*
Osteoblasts / physiology
Osteocalcin / genetics
Receptors, Calcitriol / physiology*
Vitamin D / analogs & derivatives*
Vitamin D / pharmacology

Substances

Adaptor Proteins, Signal Transducing
Glycoproteins
Intercellular Signaling Peptides and Proteins
Ligands
Receptors, Calcitriol
Sost protein, mouse
dihydroxy-vitamin D3
Osteocalcin
Vitamin D