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 VDR^ΔAF2 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.

维生素 D 受体 (VDR) 在矿物质和骨稳态的调节中发挥着关键作用。 1α,25-二羟基维生素 D ₃与 VDR 结合后，激活功能 2 (AF2) 结构域会重新定位并招募共激活因子来组装基因转录所需的转录机制。与共激活因子诱导的转录激活相反，不依赖共激活因子的 VDR 信号传导的功能效应仍不清楚。在人类中，AF2 结构域的突变与遗传性维生素 D 抗性佝偻病有关，这是一种以骨矿化和生长受损为特征的遗传性疾病。在本研究中，我们使用系统性或条件性删除 VDR-AF2 结构域 ( Vdr ^ΔAF2 ) 的小鼠来研究不依赖于共激活剂的 VDR 信号传导。我们确认配体诱导的转录激活被禁用，因为突变的 VDR ^ΔAF2蛋白无法与共激活剂相互作用。系统性Vdr ^ΔAF2小鼠发育出短的、破坏性的骨骼，具有畸形的生长板，这种骨表型比系统性Vdr敲除 ( Vdr ^−/− ) 小鼠更明显。有趣的是，富含钙、磷酸盐和乳糖的救援饮食使Vdr ^−/−小鼠的这种表型正常化，但在Vdr ^ΔAF2小鼠中则不然。然而，成骨细胞和破骨细胞特异性的Vdr ^ΔAF2小鼠并未重现这种骨表型，表明不依赖于共激活剂的 VDR 效应在其他器官中更为重要。 此外，十二指肠和肾脏的RNA测序分析显示，系统性Vdr ^ΔAF2小鼠中VDR靶基因的表达降低，而在Vdr ^−/−小鼠中未观察到这种情况。这些基因可以为矿物质的补偿（再）吸收提供新的见解，这对于骨稳态至关重要。总之，不依赖于共激活剂的 VDR 效应有助于矿物质和骨稳态。