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RANKL regulates male reproductive function

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@article{46f15d96fe214b08b62f1e48bb70cbfa,
title = "RANKL regulates male reproductive function",
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-M{\"u}llerian-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.",
keywords = "Animals, Anti-Mullerian Hormone/blood, Denosumab/pharmacology, Fertility/drug effects, Humans, Inhibins/antagonists & inhibitors, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Osteoprotegerin/pharmacology, RANK Ligand/antagonists & inhibitors, Semen/drug effects, Semen Analysis/methods, Sertoli Cells/drug effects, Sperm Count, Spermatozoa/cytology",
author = "{Blomberg Jensen}, Martin and Andreassen, {Christine Hjorth} and Anne J{\o}rgensen and Nielsen, {John Erik} and {Juel Mortensen}, Li and Boisen, {Ida Marie} and Peter Schwarz and Jorma Toppari and Roland Baron and Beate Lanske and Anders Juul",
year = "2021",
month = apr,
day = "23",
doi = "10.1038/s41467-021-22734-8",
language = "English",
volume = "12",
pages = "2450",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - RANKL regulates male reproductive function

AU - Blomberg Jensen, Martin

AU - Andreassen, Christine Hjorth

AU - Jørgensen, Anne

AU - Nielsen, John Erik

AU - Juel Mortensen, Li

AU - Boisen, Ida Marie

AU - Schwarz, Peter

AU - Toppari, Jorma

AU - Baron, Roland

AU - Lanske, Beate

AU - Juul, Anders

PY - 2021/4/23

Y1 - 2021/4/23

N2 - 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-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.

AB - 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-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.

KW - Animals

KW - Anti-Mullerian Hormone/blood

KW - Denosumab/pharmacology

KW - Fertility/drug effects

KW - Humans

KW - Inhibins/antagonists & inhibitors

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Osteoprotegerin/pharmacology

KW - RANK Ligand/antagonists & inhibitors

KW - Semen/drug effects

KW - Semen Analysis/methods

KW - Sertoli Cells/drug effects

KW - Sperm Count

KW - Spermatozoa/cytology

UR - http://www.scopus.com/inward/record.url?scp=85104855063&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-22734-8

DO - 10.1038/s41467-021-22734-8

M3 - Journal article

C2 - 33893301

VL - 12

SP - 2450

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2450

ER -

ID: 66477822