Contribution of chromosome versus gonadal sex to bone mass and strength

染色体与性腺性别对骨量和强度的影响

• 批准号: 10666647
• 负责人: Lilian Irene Plotkin
• 金额: $ 19.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666647
• 关键词: Abbreviations; Adult; Affect; Age; Age Months; Aging; Area; Bone Density; Bone Development; Bone Marrow Cells; Bone Tissue; Bone structure; Brain; Cell Count; Cell Separation; Cell physiology; Chromosomes; Distal; Exhibits; Female; Femur; Four Core Genotypes; Gender; Gene Expression; Generations; Genotype; Goals; Gonadal Steroid Hormones; Gonadal structure; Growth; Knowledge; Laboratories; Longevity; Maintenance; Marrow; Measures; Minerals; Molecular; Mus; Names; Obesity; Osteoblasts; Osteoclasts; Osteocytes; Ovary; Pattern; Persons; Phenotype; Phosphotransferases; Physiological; Protein Secretion; Proteomics; Sex Chromosomes; Sex Differences; Sexual Maturation; Signal Pathway; Skeleton; Spinal; Steroid Receptors; Structure; Testing; Testis; Thick; Tissues; Transgenes; Transgenic Organisms; Vertebral column; Work; X Chromosome; Y Chromosome; Y chromosome deletion; biomechanical test; bone; bone cell; bone health; bone loss; bone mass; bone strength; cell preparation; circulating biomarkers; cortical bone; density; dimorphism; gender dysphoria; genetic manipulation; human old age (65+); improved; male; mechanical signal; mouse model; novel; prevent; progenitor; receptor; sex; sex disparity; sexual dimorphism; single-cell RNA sequencing; skeletal; skeletal maturation; sry Genes; stem

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.

概括 在生理条件下和在基因操作之后可以看到骨骼二态性 结构、细胞和分子水平。了解这些差异的基础对于开发至关重要 专为女性和女性量身定制的预防和​​逆转骨质和强度损失的方法 男性。我们发现，与野生型雌性 C57BL/6J 小鼠相比，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较低。 1至4个月大的雄性同窝仔猪。此外，4 个月大小鼠的 µCT 分析显示 TbN 较低，并且 与雄性小鼠相比，雌性小鼠股骨远端的 TbSp 更高。 20个月差距进一步拉大 小鼠，这些参数发生变化，雌性小鼠比雄性同窝小鼠的 BV/TV 更低。同样， 男性和女性骨骼的基因操纵后果不同。骨结构的差异 两性之间的结构和组成被归因于不同的性类固醇作用。性类固醇相互作用 与骨细胞中的受体一起直接改变基因表达和细胞内激酶激活，并且独立 直接参与其他信号传导途径和机械信号。然而，性类固醇受体从骨骼中缺失 细胞尚未对两性二态性的机制提供清晰的认识。这个证据 表明性类固醇以外的因素（例如染色体性别）导致了骨骼的差异 男性和女性之间。然而，我们领域仍不清楚的一个关键问题是染色体性别是否 导致性别特异性骨骼差异。四核基因型（FCG）小鼠模型，其中睾丸 确定基因Sry从Y染色体删除和/或表达为转基因(TG)，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，但这些影响无关 性激素的存在。然而，性腺与染色体性别对骨骼发育和维持的贡献 与衰老的关系尚不清楚。我们的长期目标是了解骨性别二态性的基础，以及 性别差异如何影响骨骼的生长和衰老。我们将检验以下假设：骨量和 力量的增加和下降是性腺和染色体性别依赖性共同作用的结果 机制，通过追求 2 个目标。目标 1 我们将确定性腺与染色体的贡献 性别对 2、4 和 20 个月 FCG 小鼠骨质量和强度的影响。目标 2，将识别分子机制 通过测试 4 个月 FCG 小鼠成年骨组织性别二态性的贡献 性腺/染色体性别对骨细胞中蛋白质分泌和基因表达的影响。这些研究将推进 我们对在生长过程中以性别依赖性方式控制骨细胞功能的机制的了解，骨骼 etal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。 健康以性别依赖的方式，可能为改善维持骨骼健康的疗法提供基础 在患有性别不安的人中，循环中的性激素与染色体性别不对应。