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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

基本信息

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
项目类别：
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

项目摘要

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.

总结