Age and sex effects on FGF23-mediated response to mild phosphate challenge.
Aging
Bone
Fibroblast growth factor-23 (FGF23)
Klotho
Phosphate
Journal
Bone
ISSN: 1873-2763
Titre abrégé: Bone
Pays: United States
ID NLM: 8504048
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
23
12
2020
revised:
07
02
2021
accepted:
09
02
2021
pubmed:
23
2
2021
medline:
9
7
2021
entrez:
22
2
2021
Statut:
ppublish
Résumé
During aging, there is a normal and mild loss in kidney function that leads to abnormalities of the kidney-bone metabolic axis. In the setting of increased phosphorus intake, hyperphosphatemia can occur despite increased concentrations of the phosphaturic hormone FGF23. This is likely from decreased expression of the FGF23 co-receptor Klotho (KL) with age; however, the roles of age and sex in the homeostatic responses to mild phosphate challenges remain unclear. Male and female 16-week and 78-week mice were placed on either normal grain-based chow or casein (higher bioavailable phosphate) diets for 8 weeks. Gene expression, serum biochemistries, micro-computed tomography, and skeletal mechanics were used to assess the impact of mild phosphate challenge on multiple organ systems. Cell culture of differentiated osteoblast/osteocytes was used to test mechanisms driving key outcomes. Aging female mice responded to phosphate challenge by significantly elevating serum intact FGF23 (iFGF23) versus control diet; males did not show this response. Male mice, regardless of age, exhibited higher kidney KL mRNA with similar phosphate levels across both sexes. However, males and females had similar blood phosphate, calcium, and creatinine levels irrespective of age, suggesting that female mice upregulated FGF23 to maintain blood phosphorus, and compromised renal function could not explain the increased serum iFGF23. The 17β-estradiol levels were not different between groups, and in vivo bone steroid receptor (estrogen receptor 1 [Esr1], estrogen receptor 2 [Esr2], androgen receptor [Ar]) expression was not different by age, sex, or diet. Trabecular bone volume was higher in males but decreased with both age and phosphate challenge in both sexes. Cortical porosity increased with age in males but not females. In vitro studies demonstrated that 17β-estradiol treatment upregulated FGF23 and Esr2 mRNAs in a dose-dependent manner. Our study demonstrates that aging female mice upregulate FGF23 to a greater degree during a mild phosphate challenge to maintain blood phosphorus versus young female and young/old male mice, potentially due to direct estradiol effects on osteocytes. Thus, the control of phosphate intake during aging could have modifiable outcomes for FGF23-related phenotypes.
Sections du résumé
BACKGROUND
During aging, there is a normal and mild loss in kidney function that leads to abnormalities of the kidney-bone metabolic axis. In the setting of increased phosphorus intake, hyperphosphatemia can occur despite increased concentrations of the phosphaturic hormone FGF23. This is likely from decreased expression of the FGF23 co-receptor Klotho (KL) with age; however, the roles of age and sex in the homeostatic responses to mild phosphate challenges remain unclear.
METHODS
Male and female 16-week and 78-week mice were placed on either normal grain-based chow or casein (higher bioavailable phosphate) diets for 8 weeks. Gene expression, serum biochemistries, micro-computed tomography, and skeletal mechanics were used to assess the impact of mild phosphate challenge on multiple organ systems. Cell culture of differentiated osteoblast/osteocytes was used to test mechanisms driving key outcomes.
RESULTS
Aging female mice responded to phosphate challenge by significantly elevating serum intact FGF23 (iFGF23) versus control diet; males did not show this response. Male mice, regardless of age, exhibited higher kidney KL mRNA with similar phosphate levels across both sexes. However, males and females had similar blood phosphate, calcium, and creatinine levels irrespective of age, suggesting that female mice upregulated FGF23 to maintain blood phosphorus, and compromised renal function could not explain the increased serum iFGF23. The 17β-estradiol levels were not different between groups, and in vivo bone steroid receptor (estrogen receptor 1 [Esr1], estrogen receptor 2 [Esr2], androgen receptor [Ar]) expression was not different by age, sex, or diet. Trabecular bone volume was higher in males but decreased with both age and phosphate challenge in both sexes. Cortical porosity increased with age in males but not females. In vitro studies demonstrated that 17β-estradiol treatment upregulated FGF23 and Esr2 mRNAs in a dose-dependent manner.
CONCLUSIONS
Our study demonstrates that aging female mice upregulate FGF23 to a greater degree during a mild phosphate challenge to maintain blood phosphorus versus young female and young/old male mice, potentially due to direct estradiol effects on osteocytes. Thus, the control of phosphate intake during aging could have modifiable outcomes for FGF23-related phenotypes.
Identifiants
pubmed: 33618073
pii: S8756-3282(21)00047-8
doi: 10.1016/j.bone.2021.115885
pmc: PMC8009839
mid: NIHMS1675903
pii:
doi:
Substances chimiques
FGF23 protein, human
0
Fgf23 protein, mouse
0
Phosphates
0
Fibroblast Growth Factors
62031-54-3
Fibroblast Growth Factor-23
7Q7P4S7RRE
Glucuronidase
EC 3.2.1.31
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
115885Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL145528
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112958
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR065971
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR070329
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR074473
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR059278
Pays : United States
Organisme : NIDDK NIH HHS
ID : F31 DK122679
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
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