Genomic Mechanisms Governing Mineral Homeostasis and the Regulation and Maintenance of Vitamin D Metabolism.
Genomic Mechanisms Governing Mineral Homeostasis and the Regulation and Maintenance of Vitamin D Metabolism.
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作者：
Pike JW;Lee SM;Benkusky NA;Meyer MB
我们最近的基因组研究发现了一个复杂的肾脏特异性增强子模块，位于邻近的Mettl1 （M1）和Mettl21b （M21）基因的内含子中，介导Cyp27b1的基础和PTH诱导，以及FGF23和1,25‐二羟基维生素D3 [1,25(OH)2D3]的抑制。这种调节模块的组织特异性似乎只局限于肾近端小管。在小鼠中，这些片段的严重缺失会对骨骼健康造成严重后果，并直接影响肾脏中Cyp27b1的表达。M1和M21子模块的缺失几乎完全消除了肾脏中Cyp27b1的基础表达，创造了肾脏特异性伪空小鼠，导致与Cyp27b1‐KO小鼠相似的系统和骨骼表型，由高水平的25 -羟基维生素D3 [25(OH)D3]和PTH以及125 (OH)2D3的消耗引起。双KO小鼠的Cyp24a1水平也会下降，这是因为PTH升高和FGF23减少对该基因的代偿性下调，FGF23是由Cyp24a1基因下游的基因间模块介导的。在肾外的非肾靶细胞（nrtc）中，Cyp27b1的表达在这些突变小鼠中不受影响。饮食中钙、磷酸盐、甲状旁腺激素和FGF23的正常化挽救了这只小鼠的异常表型并使骨骼正常化。此外，在这些突变小鼠中，由于救援诱导的肾Cyp24a1正常化，高水平的25(OH)D3和低水平的125 (OH)2D3都被完全消除。因此，这些激素调节的肾脏Cyp27b1和Cyp24a1增强剂负责血液中125 (OH)2D3的循环水平。Cyp27b1和Cyp24a1在这些内分泌1,25(OH)2D3缺乏小鼠NRTC中的表达保留表明，这种Cyp27b1伪缺失小鼠将为未来探索NRTC产生的1,25(OH)2D3在健康和疾病中激素的各种非钙化作用中的作用提供模型。©2020作者。JBMR Plus由Wiley期刊有限责任公司代表美国骨骼和矿物研究协会出版。
Our recent genomic studies identified a complex kidney‐specific enhancer module located within the introns of adjacent Mettl1 (M1) and Mettl21b (M21) genes that mediate basal and PTH induction of Cyp27b1, as well as suppression by FGF23 and 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3]. The tissue specificity for this regulatory module appears to be localized exclusively to renal proximal tubules. Gross deletion of these segments in mice has severe consequences on skeletal health, and directly affects Cyp27b1 expression in the kidney. Deletion of both the M1 and M21 submodules together almost completely eliminates basal Cyp27b1 expression in the kidney, creating a renal specific pseudo‐null mouse, resulting in a systemic and skeletal phenotype similar to that of the Cyp27b1‐KO mouse caused by high levels of both 25‐hydroxyvitamin D3 [25(OH)D3] and PTH and depletion of 1,25(OH)2D3. Cyp24a1 levels in the double KO mouse also decrease because of compensatory downregulation of the gene by elevated PTH and reduced FGF23 that is mediated by an intergenic module located downstream of the Cyp24a1 gene. Outside of the kidney in nonrenal target cells (NRTCs), expression of Cyp27b1 in these mutant mice was unaffected. Dietary normalization of calcium, phosphate, PTH, and FGF23 rescues the aberrant phenotype of this mouse and normalizes the skeleton. In addition, both the high levels of 25(OH)D3 were reduced and the low levels of 1,25(OH)2D3 were fully eliminated in these mutant mice as a result of the rescue‐induced normalization of renal Cyp24a1. Thus, these hormone‐regulated enhancers for both Cyp27b1 and Cyp24a1 in the kidney are responsible for the circulating levels of 1,25(OH)2D3 in the blood. The retention of Cyp27b1 and Cyp24a1 expression in NRTCs of these endocrine 1,25(OH)2D3‐deficient mice suggests that this Cyp27b1 pseudo‐null mouse will provide a model for the future exploration of the role of NRTC‐produced 1,25(OH)2D3 in the hormone's diverse noncalcemic actions in both health and disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.