Haussler Mark R, Livingston Sarah, Sabir Zhela L, Haussler Carol A, Jurutka Peter W
Department of Basic Medical Sciences University of Arizona College of Medicine-Phoenix Phoenix AZ.
School of Mathematical and Natural Sciences Arizona State University Glendale AZ.
JBMR Plus. 2020 Dec 3;5(1):e10432. doi: 10.1002/jbm4.10432. eCollection 2021 Jan.
The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH)D], produced in kidney, acts in numerous end organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a ligand-controlled transcription factor that obligatorily heterodimerizes with retinoid X receptor (RXR) to target vitamin D responsive elements (VDREs) in the vicinity of vitamin D-regulated genes. Circulating 1,25(OH)D concentrations are governed by PTH, an inducer of renal D-hormone biosynthesis catalyzed by CYP27B1 that functions as the key player in a calcemic endocrine circuit, and by fibroblast growth factor-23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic endocrine loop. 1,25(OH)D/VDR-RXR acts in kidney to induce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, and TRPV5 and CaBP28k to enhance calcium reabsorption. 1,25(OH)D-liganded VDR-RXR functions in osteoblasts/osteocytes by augmenting RANK-ligand expression to paracrine signal osteoclastic bone resorption, while simultaneously inducing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, and TNAP, and conversely repressing RUNX2 and PHEX expression, effecting localized control of mineralization to sculpt the skeleton. Herein, we document the history of 1,25(OH)D/VDR and summarize recent advances in characterizing their physiology, biochemistry, and mechanism of action by highlighting two examples of 1,25(OH)D/VDR molecular function. The first is VDR-mediated primary induction of Klotho mRNA by 1,25(OH)D in kidney via a mechanism initiated by the docking of liganded VDR-RXR on a VDRE at -35 kb in the mouse Klotho gene. In contrast, the secondary induction of by 1,25(OH)D in bone is proposed to involve rapid nongenomic action of 1,25(OH)D/VDR to acutely activate PI3K, in turn signaling the induction of MZF1, a transcription factor that, in cooperation with c-ets1-P, binds to an enhancer element centered at -263 bp in the promoter-proximal region of the mouse gene. Chronically, 1,25(OH)D-induced osteopontin apparently potentiates MZF1. © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
激素性维生素D代谢产物1,25 - 二羟基维生素D [1,25(OH)D]在肾脏中产生，通过核维生素D受体（VDR）作用于众多终末器官，引发协调骨矿物质稳态的分子事件。VDR是一种配体控制的转录因子，它必须与视黄酸X受体（RXR）异二聚化，以靶向维生素D调节基因附近的维生素D反应元件（VDREs）。循环中的1,25(OH)D浓度受甲状旁腺激素（PTH）调控，PTH是由CYP27B1催化的肾D激素生物合成的诱导剂，在血钙内分泌回路中起关键作用；还受成纤维细胞生长因子23（FGF23）调控，FGF23是CYP27B1肾酶的抑制剂，形成一个低磷血症内分泌回路。1,25(OH)D/VDR - RXR在肾脏中发挥作用，诱导Klotho（FGF23的促尿磷排泄共受体）以纠正高磷血症，诱导NPT2a/c以纠正低磷血症，诱导TRPV5和CaBP28k以增强钙重吸收。1,25(OH)D配体化的VDR - RXR在成骨细胞/骨细胞中发挥作用，通过增加RANK配体表达以旁分泌方式信号传导破骨细胞的骨吸收，同时诱导FGF23、SPP1、BGLP、LRP5、ANK1、ENPP1和TNAP，相反抑制RUNX2和PHEX表达，实现对矿化的局部控制以塑造骨骼。在此，我们记录了1,25(OH)D/VDR的历史，并通过突出1,25(OH)D/VDR分子功能的两个例子，总结了其生理学、生物化学和作用机制表征方面的最新进展。第一个例子是1,25(OH)D在肾脏中通过配体化的VDR - RXR对接在小鼠Klotho基因 - 35 kb处的一个VDRE上启动的机制，对Klotho mRNA进行VDR介导的初级诱导。相比之下，1,25(OH)D在骨骼中对 的次级诱导被认为涉及1,25(OH)D/VDR的快速非基因组作用，以急性激活PI3K，进而信号传导诱导MZF1，MZF1是一种转录因子，它与c - ets1 - P协同作用，结合在小鼠 基因启动子近端区域以 - 263 bp为中心的增强子元件上。长期来看，1,25(OH)D诱导的骨桥蛋白显然增强了MZF1。© 2020作者。由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
