University of Ljubljana, Faculty of Pharmacy, The Chair of Clinical Biochemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
General and Teaching Hospital Celje, Department for Research and Education, Celje, Slovenia.
Exp Mol Med. 2019 Aug 14;51(8):1-16. doi: 10.1038/s12276-019-0294-3.
Receptor activator of nuclear factor κB ligand (RANKL) plays a crucial role in bone metabolism. RANKL gene misregulation has been implicated in several bone and cancer diseases. Here, we aimed to identify novel transcription regulators of RANKL expression. We discovered that transcription factors, sex-determining region Y (SRY) and c-Myb, regulate RANKL expression. We demonstrated that c-Myb increases and male-specific SRY decreases RANKL expression through direct binding to its 5'-proximal promoter. These results are corroborated by the gene expression in human bone samples. In osteoporotic men, expression of RANKL is 17-fold higher, which correlates with the drastically reduced expression (200-fold) of Sry, suggesting that in osteoporotic men, the upregulation of RANKL is caused by a decrease of Sry. In healthy men, the expression of RANKL is 20% higher than that in healthy women. Our data suggest that gender differences in RANKL expression and bone quality could be due to the sex-specific transcription factor SRY.
核因子κB 受体激活剂配体 (RANKL) 在骨代谢中起着至关重要的作用。RANKL 基因的失调与几种骨骼和癌症疾病有关。在这里，我们旨在确定 RANKL 表达的新转录调节因子。我们发现转录因子性别决定区 Y (SRY) 和 c-Myb 调节 RANKL 的表达。我们证明 c-Myb 通过直接结合其 5'-近端启动子增加 RANKL 的表达，而雄性特异性的 SRY 则减少 RANKL 的表达。这些结果得到了人类骨样本中基因表达的证实。在骨质疏松症男性中，RANKL 的表达高出 17 倍，这与 Sry 的表达急剧减少 (200 倍) 相关，表明在骨质疏松症男性中，RANKL 的上调是由于 Sry 的减少引起的。在健康男性中，RANKL 的表达比健康女性高 20%。我们的数据表明，RANKL 表达和骨质量的性别差异可能是由于性别特异性转录因子 SRY 所致。
