Group of Skeletal, Mineral and Gonadal Endocrinology, Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Division of Bone and Mineral Research, HSDM/HMS, Harvard University, Boston, MA, USA.
Nat Commun. 2021 Apr 23;12(1):2450. doi: 10.1038/s41467-021-22734-8.
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.
不育男性的治疗选择有限。在这里，我们证明了核因子-κB 受体激活剂配体（RANKL）信号系统在小鼠和人类睾丸中是活跃的。RANKL 在支持细胞中高度表达，并通过在大多数生殖细胞中表达的 RANK 信号传递，而 RANKL 抑制剂骨保护素（OPG）则在生殖细胞和成纤维细胞中表达。OPG 治疗可增加野生型小鼠的精子数量，而全身性或支持细胞特异性基因敲除 Rankl 的小鼠则具有更高的生育能力和精子数量。此外，精液中 RANKL 水平较高，与总精子计数相比，其特异性更高，可区分正常男性和不育男性。在不育男性中，单次给予地舒单抗可降低精液中 RANKL 的浓度，并增加血清抑制素-B 和抗苗勒管激素水平，但仅在亚组中改善精液质量。这项转化研究表明，RANKL 是男性生殖功能的调节剂，然而，治疗效果的预测生物标志物需要在安慰剂对照研究中进一步研究。
