Contribution of chromosome versus gonadal sex to bone mass and strength

摘要 在生理条件下和在遗传操作之后，可以在 结构、细胞和分子水平。了解这些差异的基础对于开发 专门为女性和女性量身定做的预防和扭转骨量和强度丧失的方法 男性。我们发现雌性野生型C57BL/6J小鼠的总骨密度、股骨骨密度和脊柱骨密度均低于 雄性从1到4个月龄产仔。此外，对4个月龄小鼠的µCT分析显示，总胆红素较低，并且 雌性小鼠股骨远端tbsp高于雄性小鼠。这种差异在20个月内进一步增强 随着这些参数的变化，雌性小鼠的BV/TV比雄性小鼠低。类似地， 基因操纵的后果在男性和女性骨骼中是不同的。在骨骼结构上的差异- 性别之间的真实和组成被归因于不同的性类固醇作用。性激素相互作用 通过在骨细胞中的受体直接调节基因表达和细胞内激酶的激活，并指示-1。 直接接合其他信号通路和机械信号。然而，性类固醇受体从骨骼中缺失 细胞对性二型性的机制还没有提供一个清晰的理解。这一证据 表明性别类固醇以外的因素，如染色体性别，对骨骼的差异起到了作用 在雄性和雌性之间。然而，在我们的领域中仍不清楚的一个关键问题是染色体性别 会导致不同性别的骨骼差异。四核基因(FCG)小鼠模型，在该模型中，睾丸- 决定基因Sry从Y染色体上缺失和/或表达为转基因(Tg)包括 雄性XXM(Sry TG)或XYM(YSry-/Sry TG)，雌性XXF(野生型)或XYF(YSry-)。 对这些小鼠的研究发现，染色体性别对大脑、寿命和肥胖的影响是无关的 目前存在的性激素。然而，性腺和染色体对骨骼发育和维持的贡献- 南希随着年龄的增长而不为人知。我们的长期目标是了解骨性二型性的基础，以及 性别差异如何影响不断增长和老化的骨骼。我们将检验这样的假设：骨量和 力量的增加和下降是性腺和染色体性别相关的结果 机制，通过追求两个目标。目的1我们将确定性腺对染色体的贡献 2月龄、4月龄和20月龄FCG小鼠的性别与骨量和强度的关系。目标2，将识别分子机械- 4个月龄FCG小鼠骨组织中性二型性的机制，通过测试 性腺/染色体性别对骨细胞蛋白质分泌和基因表达的影响。这些研究将取得进展 我们对在生长过程中以性别依赖的方式控制骨细胞功能的机制的了解，骨骼- 成熟期和衰退期。此外，研究结果可能会为改善骨骼的潜在方法提供信息。 以性别依赖的方式保持健康，并可能为改进治疗以保持骨骼健康提供基础 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对应。

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.