RANKL regulates male reproductive function

Author:

Blomberg Jensen MartinORCID,Andreassen Christine HjorthORCID,Jørgensen AnneORCID,Nielsen John Erik,Juel Mortensen Li,Boisen Ida Marie,Schwarz PeterORCID,Toppari Jorma,Baron RolandORCID,Lanske Beate,Juul Anders

Abstract

AbstractInfertile 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-Müllerian-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.

Funder

Rigshospitalet

Kræftens Bekæmpelse

Novo Nordisk Fonden

Sundhed og Sygdom, Det Frie Forskningsråd

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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