Influence of sex and sex hormones on modeling- and remodeling-based bone formation

性和性激素对基于建模和重塑的骨形成的影响

• 批准号: 10556506
• 负责人: Xiaowei Sherry Liu
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10556506
• 关键词: Address; Administrative Supplement; Adult; Adverse effects; Affect; Age; Anabolic Agents; Animals; Antibodies; Bone Resorption; Bone Tissue; Bone remodeling; Chronic; Chronic Disease; Coupled; Data; Deterioration; Development; Estrogens; Female; Funding; Gender; Goals; Gonadal Steroid Hormones; Hypogonadism; Investigation; Knowledge; Life; Longevity; Menopausal Status; Modeling; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis prevention; PTH gene; Patients; Periodicity; Play; Postmenopausal Osteoporosis; Postmenopause; Predisposition; Rattus; Regimen; Research; Resistance; Role; Site; Skeleton; Strategic Planning; Time; Tissues; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; Withdrawal; Woman; Women' s Health; aged; base; bone; bone loss; bone mass; clinical care; design; gonad function; improved; insight; male; mechanical properties; men; model development; novel; novel therapeutics; parathyroid hormone-related protein; parent grant; prepuberty; recruit; response; sex; skeletal; standard care; treatment duration; young adult

Project Summary The healthy skeleton continuously renews itself throughout the lifespan via closely coupled bone resorption and remodeling-based bone formation (RBF). In contrast, modeling-based bone formation (MBF), i.e., de novo bone formation without prior activation of bone resorption, is less commonly found in adults. However, MBF has been identified as an important mechanism by which anabolic agents for osteoporosis, e.g., intermittent parathyroid hormone (PTH) and PTH related peptide (PTHrP), and sclerostin antibody (Scl-Ab), rapidly elicit new bone formation. Despite the potent effect of anabolic agents on increasing bone mass, their treatment benefit can be reversed upon discontinuation. Nevertheless, osteoporosis is a life-long chronic condition and there is a pressing need for novel therapeutic regimens to enhance and maintain treatment efficacy and extend the treatment duration. Our recent investigation unexpectedly discovered that intact female and estrogen- deficient female rats had distinct responses to the discontinuation of PTH treatment. No adverse effect was observed in intact female rats, which sustained treatment benefit long after discontinuation, in contrast to the significant bone loss and bone microarchitecture deterioration observed in estrogen-deficient rats and pre- pubertal male rats after PTH discontinuation. These motivate the new objectives proposed in this supplement to further elucidate the influence of sex and gonadal function on the cellular mechanisms of MBF and RBF, which have been demonstrated to play important roles in determining skeletal responses to anabolic treatment and discontinuation. This critical knowledge will then be used to guide the novel design of a cyclic administration regimen of anabolic agents with and without intervening anti-resorptive agents to achieve the greatest treatment benefit by considering patient’s sex and gonadal function. Ovariectomized (OVX) rats will be used to simulate post-menopausal osteoporosis and orchiectomized (ORX) rats will be used to simulate hypogonadism in aged men. Age-matched, intact male and female rats will be used as young adults with intact gonadal function. We hypothesize that skeletal responses to anabolic treatment discontinuation and cyclic administration regimen are influenced by both sex and sex hormones. In the Aim 1, we will elucidate the influence of sex and sex hormones on the cellular mechanisms behind the dynamic responses of MBF and RBF to anabolic treatment discontinuation. In the Aim 2, we will optimize cyclic administration regimens of anabolic agents with and without an intervening anti-resorptive agent to achieve the best treatment efficacy based on sex and gonadal function. The proposed studies will supplement essential data regarding the influence of sex and gonadal function on development and retention of MBF and RBF to improve personalized, long-term clinical care for osteoporosis by considering patient sex and gonadal functions.

项目摘要 健康的骨骼继续通过紧密耦合的骨骼分辨率在整个生命周期内恢复自身 和基于重塑的骨形成（RBF）。相反，基于建模的骨形成（MBF），即从头开始 骨形成没有事先激活骨骼的骨骼，在成年人中很少见。但是，MBF 已被确定为一种重要的机制 甲状旁腺（PTH）和PTH相关肽（PTHRP）和硬化蛋白抗体（SCL-AB），迅速引起 新的骨形成。尽管合成代谢剂对增加骨骼的潜在影响，但它们的治疗 终止时，福利可以逆转。然而，骨质疏松症是一种终身的慢性病， 迫切需要新型的热方案以提高和维持治疗效率并延长 治疗持续时间。我们最近的调查意外发现，完整的女性和雌激素 - 不足的雌性大鼠对中断PTH治疗有明显的反应。没有不利影响是 与完整的雌性大鼠观察到，在中断后很长一段时间内维持治疗的益处 明显的骨质流失和骨微体系结构，确定在雌激素缺乏的大鼠中观察到的 PTH中断后的青春期雄性大鼠。这些激发了此补品中提出的新目标 为了进一步阐明性和性腺功能对MBF和RBF细胞机制的影响， 已经证明可以在确定对合成代谢治疗的骨骼反应中起重要作用 和中断。然后，将使用这种批判知识来指导循环的新颖设计 合成代谢剂的给药方案，有或没有干预抗敏化剂以实现 通过考虑患者的性别和性腺功能，最大的治疗益处。卵巢切除（OVX）大鼠将是 用于模拟绝经后骨质疏松症和果切除（ORX）大鼠将用于模拟 老年男性的性能。年龄匹配，完整的雄性和雌性大鼠将用作完整的年轻人 性腺功能。我们假设对中断代谢治疗的骨骼反应停用和循环 行政方案受性激素和性激素的影响。在目标1中，我们将阐明 性和性恐怖对MBF和动态反应背后的细胞机制的影响 RBF终止了合成代谢治疗。在AIM 2中，我们将优化循环给药方案 具有和没有干预剂的合成代谢剂，以达到最佳治疗效率 基于性别和性腺功能。拟议的研究将补充有关 性和性腺功能对MBF和RBF的发展和保留的影响，以改善个性化， 通过考虑患者性别和性腺功能，对骨质疏松症的长期临床护理。