Group of Skeletal, Mineral and Gonadal Endocrinology, Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA, USA.
FASEB J. 2020 Sep;34(9):12436-12449. doi: 10.1096/fj.202000061RR. Epub 2020 Jul 30.
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.
目前，大多数不孕男性的精液质量都无法得到改善。在这里，我们证明了成纤维细胞生长因子 23（FGF23）和 Klotho 的系统和直接作用，Klotho 通常调节维生素 D 和矿物质的体内平衡，对睾丸功能有直接影响。这种直接作用是合理的，因为 KLOTHO 既在生殖细胞中表达，也在精子中表达，并与 FGFR1 形成特定的受体，用于骨源性激素 FGF23。在野生型小鼠中，FGF23 的治疗增加了睾丸重量，而全身性缺失 FGF23 或 Klotho 的小鼠睾丸重量降低，精子计数和精子活力降低。具有生殖细胞特异性 Klotho（gcKL）缺陷的小鼠既没有精子计数的变化，也没有精子活力的变化。然而，检测到妊娠率降低的趋势，并且 gcKL 敲低小鼠的 Klotho 杂合子后代明显少于孟德尔遗传所预期的数量。此外，gcKL 小鼠具有分子表型，睾丸中 Slc34a2 和 Trpv5 的表达高于野生型同窝仔鼠，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 治疗增强了人类精子对孕酮的钙反应。此外，横断面数据显示，血清 Klotho 水平最高的不育男性的血清 Inhibin B 和总精子计数明显高于血清 Klotho 浓度最低的男性。总之，这项转化研究表明，FGF23 和 Klotho 通过系统改变维生素 D 和矿物质的体内平衡，直接和间接影响性腺功能和睾丸矿物质离子稳态。
