Currently, no treatment exists to improve semen quality in most infertile men. Here, we demonstrate systemic and direct effects of Fibroblast growth factor 23 (FGF23) and Klotho, which normally regulate vitamin D and mineral homeostasis, on testicular function. Direct effects are plausible because KLOTHO is expressed in both germ cells and spermatozoa and forms with FGFR1 a specific receptor for the bone‐derived hormone FGF23. Treatment with FGF23 increased testicular weight in wild‐type mice, while mice with global loss of either FGF23 or Klotho had low testicular weight, reduced sperm count, and sperm motility. Mice with germ cell‐specific Klotho (gcKL) deficiency neither had a change in sperm count nor sperm motility. However, a tendency toward fewer pregnancies was detected, and significantly fewer Klotho heterozygous pups originated from gcKL knockdown mice than would be expected by mendelian inheritance. Moreover, gcKL mice had a molecular phenotype with higher testicular expression of Slc34a2 and Trpv5 than wild‐type littermates, which suggests a regulatory role for testicular phosphate and calcium homeostasis. KLOTHO and FGFR1 were also expressed in human germ cells and spermatozoa, and FGF23 treatment augmented the calcium response to progesterone in human spermatozoa. Moreover, cross‐sectional data revealed that infertile men with the highest serum Klotho levels had significantly higher serum Inhibin B and total sperm count than men with the lowest serum Klotho concentrations. In conclusion, this translational study suggests that FGF23 and Klotho influence gonadal function and testicular mineral ion homeostasis both directly and indirectly through systemic changes in vitamin D and mineral homeostasis.

中文翻译：

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FGF23 和 Klotho 对雄性生殖的影响：系统效应与直接效应

目前，尚无改善大多数不育男性精液质量的治疗方法。在这里，我们展示了成纤维细胞生长因子 23 (FGF23) 和 Klotho（通常调节维生素 D 和矿物质稳态）对睾丸功能的全身性和直接影响。直接影响是合理的，因为 KLOTHO 在生殖细胞和精子中表达，并与 FGFR1 形成骨源性激素 FGF23 的特异性受体。FGF23 治疗增加了野生型小鼠的睾丸重量，而 FGF23 或 Klotho 整体缺失的小鼠睾丸重量低，精子数量减少，精子活力降低。具有生殖细胞特异性 Klotho (gcKL) 缺陷的小鼠精子数量和精子活力都没有变化。然而，发现有减少怀孕的趋势，来自 gcKL 敲低小鼠的 Klotho 杂合幼崽比孟德尔遗传所预期的要少得多。此外，gcKL 小鼠的分子表型 Slc34a2 和 Trpv5 的睾丸表达高于野生型同窝小鼠，这表明睾丸磷酸盐和钙稳态的调节作用。KLOTHO 和 FGFR1 也在人类生殖细胞和精子中表达，FGF23 处理增强了人类精子中对孕酮的钙反应。此外，横断面数据显示，血清 Klotho 水平最高的不育男性的血清抑制素 B 和精子总数显着高于血清 Klotho 浓度最低的男性。综上所述，