Age and sex effects on FGF23-mediated response to mild phosphate challenge
| Autor: | Pu Ni, Sharon M. Moe, Corinne E. Metzger, Megan L. Noonan, Kenneth E. White, Neal X. Chen, Matthew Prideaux, Spencer A. Sacks, Matthew R. Allen, Samantha P. Tippen, Gerald J. Atkins, William R. Thompson, Elizabeth A. Swallow |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Histology Physiology Endocrinology Diabetes and Metabolism Estrogen receptor 030209 endocrinology & metabolism Osteocytes Article Phosphates Mice 03 medical and health sciences Hyperphosphatemia chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Klotho Glucuronidase Mice Knockout Kidney Creatinine business.industry X-Ray Microtomography medicine.disease Phosphate Fibroblast Growth Factors Fibroblast Growth Factor-23 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Female business Estrogen receptor alpha Hormone |
| Zdroj: | Bone |
| ISSN: | 8756-3282 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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