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

项目摘要 健康的骨骼在整个生命周期中通过紧密结合的骨吸收不断更新自身 和基于重塑的骨形成（RBF）。相反，基于建模的骨形成（MBF），即，从头 在成年人中，在没有预先激活骨吸收的情况下骨形成是不常见的。然而，MBF 已被确定为骨质疏松症的合成代谢剂，例如，间歇 甲状旁腺激素（PTH）和PTH相关肽（PTHrP）以及硬化素抗体（Scl-Ab），迅速引起 新骨形成。尽管合成代谢剂对增加骨量有强效作用，但其治疗 停止治疗后，可恢复受益。然而，骨质疏松症是一种终身慢性疾病， 迫切需要新的治疗方案来增强和维持治疗功效并延长 治疗持续时间。我们最近的调查意外地发现完整的女性和雌激素- 缺乏PTH的雌性大鼠对停止PTH治疗有明显的反应。无不良反应， 在完整的雌性大鼠中观察到，其在停药后很长时间内持续治疗获益，与之相反， 在雌激素缺乏大鼠和雌激素缺乏前大鼠中观察到显著的骨丢失和骨微结构恶化。 PTH停药后的青春期雄性大鼠。这些激励了本补充文件中提出的新目标 为了进一步阐明性别和性腺功能对MBF和RBF的细胞机制的影响， 已经证明其在确定骨骼对合成代谢治疗的反应中起重要作用 和终止。这一关键的知识，然后将被用来指导一个循环的新颖设计， 具有和不具有干预性抗再吸收剂的合成代谢剂的施用方案，以实现 通过考虑患者的性别和性腺功能获得最大的治疗益处。卵巢切除（OVX）大鼠将 用于模拟绝经后骨质疏松症，睾丸切除（ORX）大鼠用于模拟 老年男性性腺功能减退症配对的完整雄性和雌性大鼠将用作具有完整 性腺功能我们假设骨骼对停止合成代谢治疗的反应和周期性 给药方案受性和性激素的影响。在目标1中，我们将阐明 性和性激素对MBF动态反应背后的细胞机制的影响， RBF至停止合成代谢治疗。在目标2中，我们将优化的周期性给药方案 有或没有干预性抗再吸收剂的合成代谢剂，以达到最佳治疗效果 基于性别和性腺功能拟议的研究将补充有关 性别和性腺功能对MBF和RBF发育和保持影响， 通过考虑患者性别和性腺功能，对骨质疏松症进行长期临床护理。

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.