Molecular insights into mineralotropic hormone inter-regulation
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1213361/full |
| _version_ | 1797794265404801024 |
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| author | J. Wesley Pike Seong Min Lee Mark B. Meyer |
| author_facet | J. Wesley Pike Seong Min Lee Mark B. Meyer |
| author_sort | J. Wesley Pike |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T03:00:13Z |
| format | Article |
| id | doaj.art-0c4341263d004c91b0099167fd7a91d4 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-13T03:00:13Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-0c4341263d004c91b0099167fd7a91d42023-06-27T14:48:53ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-06-011410.3389/fendo.2023.12133611213361Molecular insights into mineralotropic hormone inter-regulationJ. Wesley Pike0Seong Min Lee1Mark B. Meyer2Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United StatesDepartment of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United StatesDepartment of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United StatesThe 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.https://www.frontiersin.org/articles/10.3389/fendo.2023.1213361/fullmineral regulating hormonestranscriptionChIP-seq analysisCRISPR/Cas9mutant miceCyp27b1/Cyp24a1 genes |
| spellingShingle | J. Wesley Pike Seong Min Lee Mark B. Meyer Molecular insights into mineralotropic hormone inter-regulation Frontiers in Endocrinology mineral regulating hormones transcription ChIP-seq analysis CRISPR/Cas9 mutant mice Cyp27b1/Cyp24a1 genes |
| title | Molecular insights into mineralotropic hormone inter-regulation |
| title_full | Molecular insights into mineralotropic hormone inter-regulation |
| title_fullStr | Molecular insights into mineralotropic hormone inter-regulation |
| title_full_unstemmed | Molecular insights into mineralotropic hormone inter-regulation |
| title_short | Molecular insights into mineralotropic hormone inter-regulation |
| title_sort | molecular insights into mineralotropic hormone inter regulation |
| topic | mineral regulating hormones transcription ChIP-seq analysis CRISPR/Cas9 mutant mice Cyp27b1/Cyp24a1 genes |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1213361/full |
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