| First Author | Doms S | Year | 2024 |
| Journal | Bone Res | Volume | 12 |
| Issue | 1 | Pages | 44 |
| PubMed ID | 39164247 | Mgi Jnum | J:361101 |
| Mgi Id | MGI:7856065 | Doi | 10.1038/s41413-024-00343-7 |
| Citation | Doms S, et al. (2024) Coactivator-independent vitamin D receptor signaling causes severe rickets in mice, that is not prevented by a diet high in calcium, phosphate, and lactose. Bone Res 12(1):44 |
| abstractText | The vitamin D receptor (VDR) plays a critical role in the regulation of mineral and bone homeostasis. Upon binding of 1alpha,25-dihydroxyvitamin D(3) 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(DeltaAF2)) to study coactivator-independent VDR signaling. We confirm that ligand-induced transcriptional activation was disabled because the mutant VDR(DeltaAF2) protein was unable to interact with coactivators. Systemic Vdr(DeltaAF2) 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(DeltaAF2) mice. However, osteoblast- and osteoclast-specific Vdr(DeltaAF2) 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(DeltaAF2) 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. |
