Ga11 deficiency increases fibroblast growth factor-23 levels in a mouse model of Familial Hypocalciuric Hypercalcemia
Fibroblast Growth Factor 23 (FGF23) production has recently been shown to increase downstream of G⍺q/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding G⍺11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the impact of G⍺11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH. Strikingly, these mice also displayed increased serum levels of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and evidence of systemic inflammation with elevated serum IL1β levels. Furin gene expression was significantly increased in the Gna11-/- liver, suggesting enhanced FGF23 cleavage despite the observed rise in intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of elevated intact FGF23 levels. Thus, G⍺11 ablation caused systemic inflammation and excess serum FGF23 in mice, suggesting that FHH patients, at least those with GNA11 mutations, may be at risk for these complications.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
JCI insight - (2024) vom: 26. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ay, Birol [VerfasserIn] |
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| Links: |
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| Themen: |
Endocrinology |
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| Anmerkungen: |
Date Revised 26.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1172/jci.insight.178993 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370199278 |
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| 520 | |a Fibroblast Growth Factor 23 (FGF23) production has recently been shown to increase downstream of G⍺q/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding G⍺11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the impact of G⍺11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH. Strikingly, these mice also displayed increased serum levels of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and evidence of systemic inflammation with elevated serum IL1β levels. Furin gene expression was significantly increased in the Gna11-/- liver, suggesting enhanced FGF23 cleavage despite the observed rise in intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of elevated intact FGF23 levels. Thus, G⍺11 ablation caused systemic inflammation and excess serum FGF23 in mice, suggesting that FHH patients, at least those with GNA11 mutations, may be at risk for these complications | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a G proteins | |
| 650 | 4 | |a Genetic diseases | |
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| 700 | 1 | |a Cyr, Sajin Marcus |e verfasserin |4 aut | |
| 700 | 1 | |a Klovdahl, Kaitlin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Tognoni, Christina M |e verfasserin |4 aut | |
| 700 | 1 | |a Iwasaki, Yorihiro |e verfasserin |4 aut | |
| 700 | 1 | |a Rhee, Eugene P |e verfasserin |4 aut | |
| 700 | 1 | |a Dedeoglu, Alpaslan |e verfasserin |4 aut | |
| 700 | 1 | |a Simic, Petra |e verfasserin |4 aut | |
| 700 | 1 | |a Bastepe, Murat |e verfasserin |4 aut | |
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