Coactivator-independent vitamin D receptor signaling causes severe rickets in mice, that is not prevented by a diet high in calcium, phosphate, and lactose
Year: 2024
Type: article
Abstract: The vitamin D receptor (VDR) plays a critical role in the regulation of mineral and bone homeostasis. Upon binding of 1α,25-dihydroxyvitamin D3 to the VDR, the activation function 2 (AF2) domain repositions and recruits coactivators for the assembly of the transcriptional machinery required for gene transcription. In contrast to coactivator-induced transcriptional activation, the functional effects of coactivator-independent VDR signaling remain unclear. In humans, mutations in the AF2 domain are associated with hereditary vitamin D-resistant rickets, a genetic disorder characterized by impaired bone mineralization and growth. In the present study, we used mice with a systemic or conditional deletion of the VDR-AF2 domain (VdrΔAF2) to study coactivator-independent VDR signaling. We confirm that ligand-induced transcriptional activation was disabled because the mutant VDRΔAF2 protein was unable to interact with coactivators. Systemic VdrΔAF2 mice developed short, undermineralized bones with dysmorphic growth plates, a bone phenotype that was more pronounced than that of systemic Vdr knockout (Vdr-/-) mice. Interestingly, a rescue diet that is high in calcium, phosphate, and lactose, normalized this phenotype in Vdr-/-, but not in VdrΔAF2 mice. However, osteoblast- and osteoclast-specific VdrΔAF2 mice did not recapitulate this bone phenotype indicating coactivator-independent VDR effects are more important in other organs. In addition, RNA-sequencing analysis of duodenum and kidney revealed a decreased expression of VDR target genes in systemic VdrΔAF2 mice, which was not observed in Vdr-/- mice. These genes could provide new insights in the compensatory (re)absorption of minerals that are crucial for bone homeostasis. In summary, coactivator-independent VDR effects contribute to mineral and bone homeostasis.
Source: Bone Research
Institutions: KU Leuven, RWTH Aachen University, IRYO Sosei University
Language: English
Topic: Vitamin D Research Studies
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,405
Awards: The role of the kidney in vitamin D synthesis and vitamin D mediated calcium and phosphate handling., Unravelling the versatile transcriptionally repressive effects of the vitamin D receptor, highlighting the regulation of calcium and energy homeostasis., Unraveling the ligand-independent signaling of the vitamin D receptor, The beta-cell and the immune system in type 1 diabetes: partners in crime - developing new therapies in type 1 diabetes through better understanding of beta-cell behaviour and use of novel immunomodulators., G7124197110
OpenAlex ID: W4401729412