NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH
PTH induces phosphorylation of the transcriptional coregulator NACA on serine 99 through Gαs and PKA. This leads to nuclear translocation of NACA and expression of the target gene <i>Lrp6</i>, encoding a coreceptor of the PTH receptor (PTH1R) necessary for full anabolic response to inter...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/2/940 |
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| author | René St-Arnaud Martin Pellicelli Mahmoud Ismail Alice Arabian Toghrul Jafarov Chengji J. Zhou |
| author_facet | René St-Arnaud Martin Pellicelli Mahmoud Ismail Alice Arabian Toghrul Jafarov Chengji J. Zhou |
| author_sort | René St-Arnaud |
| collection | DOAJ |
| description | PTH induces phosphorylation of the transcriptional coregulator NACA on serine 99 through Gαs and PKA. This leads to nuclear translocation of NACA and expression of the target gene <i>Lrp6</i>, encoding a coreceptor of the PTH receptor (PTH1R) necessary for full anabolic response to intermittent PTH (iPTH) treatment. We hypothesized that maintaining enough functional PTH1R/LRP6 coreceptor complexes at the plasma membrane through NACA-dependent <i>Lrp6</i> transcription is important to ensure maximal response to iPTH. To test this model, we generated compound heterozygous mice in which one allele each of <i>Naca</i> and <i>Lrp6</i> is inactivated in osteoblasts and osteocytes, using a knock-in strain with a <i>Naca</i><sup>99</sup> Ser-to-Ala mutation and an <i>Lrp6</i> floxed strain (test genotype: <i>Naca</i><sup>99S/A</sup>; <i>Lrp6</i><sup>+/fl</sup>;OCN-Cre). Four-month-old females were injected with vehicle or 100 μg/kg PTH(1-34) once daily, 5 days a week for 4 weeks. Control mice showed significant increases in vertebral trabecular bone mass and biomechanical properties that were abolished in compound heterozygotes. <i>Lrp6</i> expression was reduced in compound heterozygotes vs. controls. The iPTH treatment increased <i>Alpl</i> and <i>Col1a1</i> mRNA levels in the control but not in the test group. These results confirm that NACA and LRP6 form part of a common genetic pathway that is necessary for the full anabolic effect of iPTH. |
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| language | English |
| last_indexed | 2024-03-10T01:17:29Z |
| publishDate | 2022-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cfb112648d7f47778057fe62e424913a2023-11-23T14:06:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-0123294010.3390/ijms23020940NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTHRené St-Arnaud0Martin Pellicelli1Mahmoud Ismail2Alice Arabian3Toghrul Jafarov4Chengji J. Zhou5Research Centre, Shriners Hospital for Children—Canada, Montreal, QC H4A 0A9, CanadaResearch Centre, Shriners Hospital for Children—Canada, Montreal, QC H4A 0A9, CanadaResearch Centre, Shriners Hospital for Children—Canada, Montreal, QC H4A 0A9, CanadaResearch Centre, Shriners Hospital for Children—Canada, Montreal, QC H4A 0A9, CanadaResearch Centre, Shriners Hospital for Children—Canada, Montreal, QC H4A 0A9, CanadaDepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USAPTH induces phosphorylation of the transcriptional coregulator NACA on serine 99 through Gαs and PKA. This leads to nuclear translocation of NACA and expression of the target gene <i>Lrp6</i>, encoding a coreceptor of the PTH receptor (PTH1R) necessary for full anabolic response to intermittent PTH (iPTH) treatment. We hypothesized that maintaining enough functional PTH1R/LRP6 coreceptor complexes at the plasma membrane through NACA-dependent <i>Lrp6</i> transcription is important to ensure maximal response to iPTH. To test this model, we generated compound heterozygous mice in which one allele each of <i>Naca</i> and <i>Lrp6</i> is inactivated in osteoblasts and osteocytes, using a knock-in strain with a <i>Naca</i><sup>99</sup> Ser-to-Ala mutation and an <i>Lrp6</i> floxed strain (test genotype: <i>Naca</i><sup>99S/A</sup>; <i>Lrp6</i><sup>+/fl</sup>;OCN-Cre). Four-month-old females were injected with vehicle or 100 μg/kg PTH(1-34) once daily, 5 days a week for 4 weeks. Control mice showed significant increases in vertebral trabecular bone mass and biomechanical properties that were abolished in compound heterozygotes. <i>Lrp6</i> expression was reduced in compound heterozygotes vs. controls. The iPTH treatment increased <i>Alpl</i> and <i>Col1a1</i> mRNA levels in the control but not in the test group. These results confirm that NACA and LRP6 form part of a common genetic pathway that is necessary for the full anabolic effect of iPTH.https://www.mdpi.com/1422-0067/23/2/940NACALRP6parathyroid hormoneosteoblastsosteocytesbone |
| spellingShingle | René St-Arnaud Martin Pellicelli Mahmoud Ismail Alice Arabian Toghrul Jafarov Chengji J. Zhou NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH International Journal of Molecular Sciences NACA LRP6 parathyroid hormone osteoblasts osteocytes bone |
| title | NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH |
| title_full | NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH |
| title_fullStr | NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH |
| title_full_unstemmed | NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH |
| title_short | NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH |
| title_sort | naca and lrp6 are part of a common genetic pathway necessary for full anabolic response to intermittent pth |
| topic | NACA LRP6 parathyroid hormone osteoblasts osteocytes bone |
| url | https://www.mdpi.com/1422-0067/23/2/940 |
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