Contribution of chromosome versus gonadal sex to bone mass and strength

总结 在生理条件下和在基因操作后，可以看到骨骼二型性。 结构、细胞和分子水平。了解这些差异的基础对于开发 专门为女性量身定制的预防和逆转骨量和强度损失的方法， 男性。我们已经显示，与对照组相比，雌性野生型C57 BL/6 J小鼠的总BMD、股骨BMD和脊柱BMD较低。 1至4个月大的雄性同窝仔。此外，4个月小鼠的µCT分析显示TbN较低， 雌性小鼠股骨远端TbSp高于雄性小鼠。在20个月内，这种差异进一步扩大 与同窝雄性小鼠相比，雌性小鼠的这些参数发生变化，BV/TV较低。类似地， 基因操作的结果在男性和女性骨骼之间是不同的。骨结构的差异- 性别之间的真实性和组成被归因于不同的性类固醇作用。性类固醇相互作用 与骨细胞中的受体直接修饰基因表达和细胞内激酶活化，并诱导 直接参与其他信号通路和机械信号。然而，性类固醇受体从骨中缺失 细胞还没有提供一个明确的了解机制的两性异形。这一证据 表明除了性类固醇以外的其他因素，如染色体性别，也会导致骨骼的差异。 男性和女性之间。然而，在我们的领域中仍然不清楚的一个关键问题是染色体性别是否 导致了性别特异性骨骼差异。四核心基因型（FCG）小鼠模型，其中睾丸- 确定基因Sry从Y染色体缺失和/或表达为转基因（TG）的方法包括 2种性腺性别的小鼠：雄性XXM（Sry TG）或XYM（YSry-/Sry TG），以及雌性XXF（野生型）或XYF（YSry-）。 对这些小鼠的研究揭示了染色体性别对大脑、寿命和肥胖的影响， 性激素的反应然而，性腺与染色体性别对骨骼发育和维持的贡献 与衰老的关系是未知的。我们的长期目标是了解骨骼两性异形的基础， 性别差异如何影响骨骼的生长和衰老。我们将检验骨量和 性腺和染色体性别依赖性共同作用导致力量的增加和下降 #21453;，追求两个目标。目的1我们将确定性腺与染色体的贡献 性别与2个月、4个月和20个月FCG小鼠的骨量和强度。目标2，将识别分子机械- 在4个月的FCG小鼠成年骨组织中，通过测试 性腺/染色体性别与骨细胞中蛋白质分泌和基因表达的关系。这些研究将进一步 我们对生长过程中以性别依赖方式控制骨细胞功能的机制的了解， 埃塔尔成熟和老化。此外，研究结果可以为改善骨骼的潜在方法提供信息。 以性别依赖的方式促进骨骼健康，并可能为改善维持骨骼健康的疗法提供基础。 在患有性别焦虑症的人中，循环中的性激素与染色体性别不一致。

SUMMARY Skeletal dimorphism can be seen under physiological conditions and following genetic manipulations at the structural, cellular, and molecular levels. Understanding the basis for these differences is crucial to developing approaches to prevent and reverse the loss of bone mass and strength, tailored specifically for females and males. We have shown lower total, femoral, and spinal BMD in female wild type C57BL/6J mice compared to male littermates from 1 to 4 months of age. Further, µCT analysis in 4-months mice showed lower TbN, and higher TbSp in distal femur of female compared to male mice. The differences are further enhanced in 20-months mice, with changes in these parameters and lower BV/TV in female mice versus male littermates. Similarly, the consequences of genetic manipulations differ between male and female skeleton. The difference in bone struc- ture and composition between sexes has been ascribed to disparate sex steroid actions. Sex steroids interact with their receptors in bone cells to directly modify gene expression and intracellular kinase activation, and indi- rectly engage other signaling pathways and mechanical signals. Yet, sex steroid receptors deletion from bone cells has not provided a clear understanding of the mechanisms underlying sexual dimorphism. This evidence suggests that factors other than sex steroids such as chromosome sex contribute to the differences in bone between males and females. Yet, a key question that remains unclear in our field is whether chromosome sex contributes to sex-specific skeletal differences. The four-core genotype (FCG) mouse model, in which the testis- determining gene Sry was deleted from the Y chromosome and/or expressed as a transgene (TG) comprises mice of 2 gonadal sexes: male XXM (Sry TG) or XYM (YSry-/Sry TG), and female XXF (wild type) or XYF (YSry-). Studies with these mice uncovered chromosome sex effects on the brain, on lifespan, and on adiposity, unrelated to the sex hormone present. Yet, gonadal versus chromosome sex contribution to bone development and mainte- nance with aging is unknown. Our long-term goal is to understand the basis for bone sexual dimorphism, and how sex differences affect the growing and aging skeleton. We will test the hypothesis that bone mass and strength accrual and decline result from a combination of gonadal and chromosome sex-dependent mechanisms, by pursuing 2 Aims. Aim 1 we will determine the contribution of gonadal versus chromosome sex to bone mass and strength in 2-, 4-, and 20-months FCG mice. Aim 2, will identify the molecular mech- anism for sexual dimorphism in adult bone tissue in 4-months FCG mice, by testing the contribution of the gonadal/chromosome sex to protein secretion and gene expression in bone cells. These studies will advance our knowledge of the mechanisms controlling bone cell function in a sex-dependent manner during growth, skel- etal maturation, and aging. Further, the results of the studies could inform on potential ways to improve bone health in a gender dependent manner and might provide the basis for improved therapies to maintain bone health in people with gender dysphoria, with circulating sex hormones that do not correspond to the chromosome sex.