Babey Muriel E, Krause William C, Herber Candice B, Chen Kun, Nikkanen Joni, Rodriquez Ruben, Zhang Xiao, Castro-Navarro Fernanda, Wang Yuting, Villeda Saul, Lane Nancy E, Scheller Erica L, Chan Charles K F, Ambrosi Thomas H, Ingraham Holly A
bioRxiv. 2023 Nov 16:2023.08.28.554707. doi: 10.1101/2023.08.28.554707.
In lactating mothers, the high calcium (Ca ) demand for milk production triggers significant bone resorption. While estrogen would normally counteract excessive bone loss and maintain sufficient bone formation during this postpartum period, this sex steroid drops precipitously after giving birth. Here, we report that brain-derived CCN3 (Cellular Communication Network factor 3) secreted from KISS1 neurons of the arcuate nucleus (ARC ) fills this void and functions as a potent osteoanabolic factor to promote bone mass in lactating females. Using parabiosis and bone transplant methods, we first established that a humoral factor accounts for the female-specific, high bone mass previously observed by our group after deleting estrogen receptor alpha (ER ) from ARC neurons . This exceptional bone phenotype in mutant females can be traced back to skeletal stem cells (SSCs), as reflected by their increased frequency and osteochondrogenic potential. Based on multiple assays, CCN3 emerged as the most promising secreted pro-osteogenic factor from ARC neurons, acting on mouse and human SSCs at low subnanomolar concentrations independent of age or sex. That brain-derived CCN3 promotes bone formation was further confirmed by in vivo gain- and loss-of-function studies. Notably, a transient rise in CCN3 appears in ARC neurons in estrogen-depleted lactating females coincident with increased bone remodeling and high calcium demand. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone that defines a novel female-specific brain-bone axis for ensuring mammalian species survival.
在哺乳期母亲中，产奶对钙的高需求会引发显著的骨吸收。虽然雌激素通常会在产后期间抵消过度的骨质流失并维持足够的骨形成，但这种性类固醇在分娩后会急剧下降。在此，我们报告称，从弓状核（ARC）的KISS1神经元分泌的脑源性CCN3（细胞通讯网络因子3）填补了这一空白，并作为一种强大的骨合成代谢因子发挥作用，以促进哺乳期雌性动物的骨量。使用联体生活和骨移植方法，我们首先确定了一种体液因子是我们小组先前从ARC神经元中删除雌激素受体α（ERα）后观察到的雌性特异性高骨量的原因。突变雌性动物中这种特殊的骨表型可追溯到骨骼干细胞（SSCs），这反映在它们增加的频率和成骨软骨生成潜力上。基于多项检测，CCN3成为ARC神经元中最有希望的分泌型促骨生成因子，在低亚纳摩尔浓度下作用于小鼠和人类的SSCs，与年龄或性别无关。体内功能获得和功能丧失研究进一步证实了脑源性CCN3促进骨形成。值得注意的是，在雌激素缺乏的哺乳期雌性动物的ARC神经元中，CCN3会短暂升高，这与骨重塑增加和高钙需求同时出现。我们的研究结果将CCN3确立为一种潜在的新型治疗性骨合成代谢激素，它定义了一条新的雌性特异性脑-骨轴，以确保哺乳动物物种的生存。
