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.
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.
J Steroid Biochem Mol Biol. 2018 Mar;177:83-90. doi: 10.1016/j.jsbmb.2017.09.005. Epub 2017 Sep 6.
Previous studies have shown that 1α,25-dihydroxyvitamin D (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.
先前的研究表明，1α，25-二羟维生素 D（1，25D）通过维生素 D 受体（VDR）信号传导对成骨细胞分化具有分解代谢和合成代谢作用。然而，1，25D 产生这些差异作用的机制尚未完全阐明。在这项研究中，利用具有三种不同遗传背景的小鼠，代表正常 VDR 水平（野生型，WT）、特异性在成熟成骨细胞中过表达的 VDR（ObVDR-B6）和全球 VDR 敲除（VDRKO），生成原代成骨细胞样培养物，以进一步阐明 1，25D 对成骨细胞分化的影响。我们的数据证实了 VDR 在成骨分化后期以及对成骨细胞支持破骨细胞形成的关键因子表达的重要性。这项研究还表明，药理学水平的 1，25D（1nM）对成骨分化标志物的表达具有差异作用，包括 Ocn 和 Sost，这取决于 VDR 的相对水平。我们的发现表明，1，25D 通过调节组织非特异性碱性磷酸酶到外核苷酸焦磷酸酶/磷酸二酯酶 1 轴，在 VDR 水平依赖性方式中，在基质矿化中发挥抑制作用。我们得出结论，相对 VDR 水平和细胞中 1，25D 的可用性是 1，25D 在成骨细胞介导的成骨活性中发挥促进或抑制作用的重要共同决定因素。
