Influence of FGF23 and Klotho on male reproduction: Systemic vs direct effects

Abstract

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.

Changes in local mineral homeostasis facilitate the formation of benign and malignant testicular microcalcifications

“…The epididymal phenotype of Fgf23 -/- mice does not appear to be mediated via systemic hyperphosphatemia as a high phosphate dietary exposure for weeks did not result in testicular or epididymal microcalcifications or changes in testicular phosphate transporter expression. Instead, we have previously shown that germ cell-specific deletion of Klotho in mice leads to aberrant mineral homeostasis, particularly calcium transport through TRPV5 42 , which may be important as low calcium appears to be protective for inducing microcalcifications in a high phosphate environment. Local testicular mineral levels depend mainly on the presence and activity of specific transporters and sensors of calcium and phosphate in the reproductive organs, rather than on systemic concentrations 43 .…”

“…Human iFGF23 and total FGF23 (iFGF23 + cFGF23) were measured in duplicates in batched assays using assays from Immutopics (Immutopics, #60-6100, #60-6600) according to the manufacturer’s instructions. The seminal fluid FGF23 measurements in healthy men have been published previously 42 . Total serum calcium and phosphorus levels were determined using Stanbio LiquiColor Kits (Stanbio Laboratory).…”

Advanced Paternal Age and Future Generations

“…Several inbred strains of mice, such as the senescence-accelerated mouse ( 10 , 11 ), and transgenic mice, such as Klotho mice ( 12 , 13 ), have been developed to model accelerated aging in humans. These mice exhibit defects in a wide range of organs (e.g., vessels, lungs, kidney, brain, skin and testes), and thus are poor models to study aging of male germ cells as many interfering systems could be operant.…”

Klotho’s impact on diabetic nephropathy and its emerging connection to diabetic retinopathy

“…Genetic defects in klotho have been found to cause vascular calcification, hyperphosphatemia, nephropathy, growth retardation, multi-organ atrophy, and fibrosis ( 8 – 10 ). Expression of klotho has been detected mainly in the kidney, brain, and pancreas, but also in human germ cells and sperm ( 11 ). The klotho family consists of three members: α-, β-, and γ-klotho ( 12 ).…”