A1 Refereed original research article in a scientific journal

RANKL regulates male reproductive function




AuthorsJensen Martin Blomberg, Andreassen Christine Hjorth, Jørgensen Anne, Nielsen John Erik, Mortensen Li Juel, Boisen Ida Marie, Schwarz Peter, Toppari Jorma, Baron Roland, Lanske Beate, Juul Anders

PublisherNATURE RESEARCH

Publication year2021

JournalNature Communications

Journal name in sourceNATURE COMMUNICATIONS

Journal acronymNAT COMMUN

Article numberARTN 2450

Volume12

Issue1

Number of pages15

ISSN2041-1723

eISSN 2041-1723

DOIhttps://doi.org/10.1038/s41467-021-22734-8

Web address https://www.nature.com/articles/s41467-021-22734-8

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/66382573


Abstract

Infertile men have few treatment options. Here, we demonstrate that the transmembrane receptor activator of NF-kB ligand (RANKL) signaling system is active in mouse and human testis. RANKL is highly expressed in Sertoli cells and signals through RANK, expressed in most germ cells, whereas the RANKL-inhibitor osteoprotegerin (OPG) is expressed in germ and peritubular cells. OPG treatment increases wild-type mouse sperm counts, and mice with global or Sertoli-specific genetic suppression of Rankl have increased male fertility and sperm counts. Moreover, RANKL levels in seminal fluid are high and distinguishes normal from infertile men with higher specificity than total sperm count. In infertile men, one dose of Denosumab decreases RANKL seminal fluid concentration and increases serum Inhibin-B and anti-Mullerian-hormone levels, but semen quality only in a subgroup. This translational study suggests that RANKL is a regulator of male reproductive function, however, predictive biomarkers for treatment-outcome requires further investigation in placebo-controlled studies. There are few treatments for male infertility. Here, the authors show that the receptor activator of NF-kappa B ligand (RANKL) signalling pathway has important functions in sperm production and maturation, improves fertility in male mice and shows potential as a male infertility target.


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