Abstract
The vitamin D receptor (VDR) mediates vitamin D actions beyond bone health. While VDR activation by 1,25-dihydroxyvitamin D (1,25D) leads to robust transcriptional regulation, less is known about VDR actions in the absence of 1,25D. We analyzed the transcriptomic response to 1,25D in fibroblasts bearing a severe homozygous hereditary vitamin D resistant rickets-related p.Arg30* VDR mutation (MUT) and in control fibroblasts (CO). Roughly 4.5% of the transcriptome was regulated by 1,25D in CO fibroblasts, while MUT cells without a functional VDR were insensitive to 1,25D. Novel VDR target genes identified in human fibroblasts included bone and cartilage factors CILP, EFNB2, and GALNT12. Vehicle-treated CO and MUT fibroblasts had strikingly different transcriptomes, suggesting basal VDR activity. Indeed, oppositional transcriptional effects in basal conditions versus after 1,25D activation were implied for a subset of target genes mostly involved with cell cycle. Cell proliferation assays corroborated this conjectured oppositional basal VDR activity, indicating that precise 1,25D dosage in target tissues might be essential for modulating vitamin D actions in human health.
Highlights
The vitamin D receptor (VDR, NR1I1) is a nuclear receptor transcription factor that acts as the main physiologic transducer of vitamin D actions at the cellular level [1,2]
Human skin fibroblasts from the hereditary vitamin D-resistant rickets (HVDRR) patient with a homozygous p.Arg30* VDR mutation [21,22] and from an age/sex-matched control were obtained from 4 mm punch biopsies of the forearm skin after institutional board approval and with informed consent
Transcriptomic microarray analysis of control fibroblasts (CO) and MUT fibroblasts after 24 h cells
Summary
The vitamin D receptor (VDR, NR1I1) is a nuclear receptor transcription factor that acts as the main physiologic transducer of vitamin D actions at the cellular level [1,2]. VDR activation by its high-affinity ligand 1,25-dihydroxyvitamin D (1,25D) leads to transcriptional regulation of numerous target genes and modification of the cellular transcriptomic. D target organs such as intestine and bone, VDR expression in several cell types beyond those directly involved in mineral homeostasis have prompted great interest [1]. VDR expression in such tissues has provided a solid ground for investigating multiple vitamin D actions across human health besides the regulation of bone and mineral homeostasis, in light of well demonstrated extrarenal 1α-hydroxylase activity and consequent 1,25D availability in a paracrine or autocrine fashion [9,10,11]. The unliganded VDR could be acting in these cells in the absence of 1,25D stimulus, regulating basal gene expression or in response to other stimuli. Based on phenotypic observation of human and mice VDR defects, a role for the unliganded VDR has been identified in, for example, the hair follicle [1,12]
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