矿物质稳态的调节涉及三种促矿物质激素PTH,FGF23和1,25-二羟基维生素D3(1,25(OH)2D3)。早期的研究工作集中在PTH和1,25(OH)2D3上,最近在FGF23上,已经表明这些激素中的每一种调节其他两种的表达。尽管早期有转录过程的建议,直到最近,研究工作才开始描绘支持1,25(OH)2D3和FGF23调节的基因组机制;然而,1,25(OH)2D3对PTH的调节,仍然晦涩难懂。我们在这里回顾了我们对PTH如何诱导Cyp27b1表达的分子理解,编码负责合成1,25(OH)2D3的酶的基因。另一方面,FGF23和1,25(OH)2D3,通过抑制1,25(OH)2D3的产生起作用。PTH在Cyp27b1的肾脏特异性调节区域内的CREB占据位点刺激PKA诱导的CREB及其共激活剂CBP的募集。PKA活化还促进SIK结合的共激活剂如CRTC2的核易位,其中它类似地与CREB占据的Cyp27b1位点相互作用。FGF23和1,25(OH)2D3的负作用似乎通过反对该基因上CREB共激活剂的募集来抑制Cyp27b1的表达。在Cyp24a1可以看到相互的基因作用,该基因编码降解1,25(OH)2D3的酶,从而有助于1,25(OH)2D3的血液水平的整体调节。相对于PTH调节,我们总结了已知的1,25(OH)2D3如何调节PTH抑制。这些研究表明,不是1,25(OH)2D3控制健康受试者的PTH水平,而是钙本身。最后,我们使用体内方法描述了当前的进展,该方法进一步加深了我们对PTH和1,25(OH)2D3对Fgf23表达的调节的理解,并提供了第一个证据表明P可能通过骨骼中复杂的转录机制诱导Fgf23表达。很清楚,然而,需要进一步的进步来进一步理解这些激素基因的相互调节。
The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Early research efforts focused on PTH and 1,25(OH)2D3 and more recently on FGF23 have revealed that each of these hormones regulates the expression of the other two. Despite early suggestions of transcriptional processes, it has been only recently that research effort have begun to delineate the genomic mechanisms underpinning this regulation for 1,25(OH)2D3 and FGF23; the regulation of PTH by 1,25(OH)2D3, however, remains obscure. We review here our molecular understanding of how PTH induces Cyp27b1 expression, the gene encoding the enzyme responsible for the synthesis of 1,25(OH)2D3. FGF23 and 1,25(OH)2D3, on the other hand, function by suppressing production of 1,25(OH)2D3. PTH stimulates the PKA-induced recruitment of CREB and its coactivator CBP at CREB occupied sites within the kidney-specific regulatory regions of Cyp27b1. PKA activation also promotes the nuclear translocation of SIK bound coactivators such as CRTC2, where it similarly interacts with CREB occupied Cyp27b1 sites. The negative actions of both FGF23 and 1,25(OH)2D3 appear to suppress Cyp27b1 expression by opposing the recruitment of CREB coactivators at this gene. Reciprocal gene actions are seen at Cyp24a1, the gene encoding the enzyme that degrades 1,25(OH)2D3, thereby contributing to the overall regulation of blood levels of 1,25(OH)2D3. Relative to PTH regulation, we summarize what is known of how 1,25(OH)2D3 regulates PTH suppression. These studies suggest that it is not 1,25(OH)2D3 that controls PTH levels in healthy subjects, but rather calcium itself. Finally, we describe current progress using an in vivo approach that furthers our understanding of the regulation of Fgf23 expression by PTH and 1,25(OH)2D3 and provide the first evidence that P may act to induce Fgf23 expression via a complex transcriptional mechanism in bone. It is clear, however, that additional advances will need to be made to further our understanding of the inter-regulation of each of these hormonal genes.