Department of Genetics and Development, Columbia University, New York, New York, USA.
J Clin Invest. 2013 Jun;123(6):2421-33. doi: 10.1172/JCI65952.
The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates osteocalcin's reproductive effects. Additionally, there is growing evidence that osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of osteocalcin is unclear. Using mouse models, we found that osteocalcin and LH act in 2 parallel pathways and that osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans.
成骨细胞衍生的激素骨钙素通过与莱迪希细胞中的 GPRC6A 结合，促进小鼠睾丸中的睾丸激素生物合成。有趣的是，骨钙素缺乏的小鼠表现出促黄体激素 (LH) 水平升高，LH 是一种调节睾丸中类固醇合成的垂体激素。这些观察结果提出了一个问题，即 LH 是否调节骨钙素的生殖作用。此外，越来越多的证据表明，骨钙素水平是人类胰岛素分泌和敏感性以及循环睾丸激素的可靠标志物，但骨钙素的内分泌功能尚不清楚。使用小鼠模型，我们发现骨钙素和 LH 在 2 条平行途径中起作用，并且骨钙素刺激的睾丸激素合成受到成骨细胞中骨吸收和胰岛素信号的正向调节。为了确定骨钙素在人类中的重要性，我们分析了一组原发性睾丸功能衰竭患者，并鉴定出 2 名个体携带 GPRC6A 一个跨膜结构域中的相同杂合错义变异，该变异阻止受体定位于细胞膜。这项研究揭示了在小鼠中存在第二个内分泌轴，这对于最佳男性生育力是必要的，并表明骨钙素在人类中调节生殖功能。
