Coactivator-independent vitamin D receptor signaling causes severe rickets in mice, that is not prevented by a diet high in calcium, phosphate, and lactose

Autor: Stefanie Doms, Lieve Verlinden, Iris Janssens, Justine Vanhevel, Roy Eerlings, René Houtman, Shigeaki Kato, Chantal Mathieu, Brigitte Decallonne, Geert Carmeliet, Annemieke Verstuyf
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Bone Research, Vol 12, Iss 1, Pp 1-13 (2024)
Druh dokumentu: article
ISSN: 2095-6231
DOI: 10.1038/s41413-024-00343-7
Popis: 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 (Vdr ΔAF2 ) 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 Vdr ΔAF2 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 Vdr ΔAF2 mice. However, osteoblast- and osteoclast-specific Vdr ΔAF2 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 Vdr ΔAF2 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.
Databáze: Directory of Open Access Journals
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