Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Bone. 2021 May;146:115885. doi: 10.1016/j.bone.2021.115885. Epub 2021 Feb 19.
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.
随着年龄的增长，肾功能会出现正常且轻微的丧失，从而导致肾脏-骨骼代谢轴的异常。在磷摄入量增加的情况下，尽管甲状旁腺激素 FGF23 浓度升高，仍可能发生高磷血症。这可能是由于年龄增长导致 FGF23 辅助受体 Klotho (KL) 的表达减少所致；然而，年龄和性别在轻度磷酸盐挑战的体内平衡反应中的作用仍不清楚。
16 周和 78 周龄的雄性和雌性小鼠分别给予正常谷物基础饲料或酪蛋白（生物利用度更高的磷）饮食 8 周。使用基因表达、血清生化、微计算机断层扫描和骨骼力学来评估轻度磷酸盐挑战对多个器官系统的影响。分化的成骨细胞/成骨细胞的细胞培养用于测试驱动关键结果的机制。
与对照饮食相比，老年雌性小鼠对磷酸盐挑战的反应是显著升高血清完整 FGF23 (iFGF23)；而雄性小鼠则没有这种反应。无论年龄大小，雄性小鼠的肾脏 KL mRNA 水平都较高，而两性的磷酸盐水平相似。然而，无论年龄大小，雄性和雌性的血液磷酸盐、钙和肌酐水平相似，表明雌性小鼠上调 FGF23 以维持血液磷，而肾功能受损不能解释血清 iFGF23 的增加。各组间 17β-雌二醇水平无差异，且体内骨类固醇受体（雌激素受体 1 [Esr1]、雌激素受体 2 [Esr2]、雄激素受体 [Ar]）表达不因年龄、性别或饮食而不同。与年轻雌性和年轻/老年雄性小鼠相比，雄性小鼠的小梁骨体积较高，但在两性中均随年龄和磷酸盐挑战而降低。雄性的皮质骨孔隙度随年龄增加而增加，但雌性则不然。体外研究表明，17β-雌二醇以剂量依赖性方式上调 FGF23 和 Esr2 mRNA。
我们的研究表明，在轻度磷酸盐挑战期间，老年雌性小鼠上调 FGF23 的程度大于年轻雌性和年轻/老年雄性小鼠，以维持血液磷，这可能是由于雌二醇对破骨细胞的直接作用。因此，在衰老过程中控制磷酸盐摄入可能对与 FGF23 相关的表型具有可调节的作用。
