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

项目摘要 健康的骨骼通过紧密结合的骨吸收在整个生命周期中不断更新自己 和基于改建的骨形成(RBF)。相比之下，基于模型的骨形成(MBF)，即从头开始 没有预先激活骨吸收的骨形成在成人中较少见。然而，MBF 已被确认为治疗骨质疏松症的合成代谢剂，例如间歇性的 甲状旁腺激素(PTH)和甲状旁腺激素相关肽(PTHrP)，以及硬化素抗体(scl-Ab)快速诱导 新骨形成。尽管合成代谢药物在增加骨量方面有很强的作用，但它们的治疗 福利可以在终止时逆转。然而，骨质疏松症是一种终生的慢性疾病， 迫切需要新的治疗方案来增强和维持治疗效果并扩大 治疗持续时间。我们最近的调查出人意料地发现，完整的女性和雌激素- 缺陷型雌性大鼠对停止PTH治疗有明显的反应。未见不良反应。 在完好的雌性大鼠中观察到，在停药后很长一段时间内持续治疗受益，而不是 在雌激素缺乏的大鼠和高血压前期，观察到显著的骨丢失和骨微结构恶化。 停用甲状旁腺素后青春期雄性大鼠。这些激励了本补编中提出的新目标 为了进一步阐明性别和性腺功能对MBF和RBF细胞机制的影响， 它们已被证明在决定骨骼对合成代谢治疗的反应中起着重要作用 和停产。然后，这些关键知识将被用于指导循环的新设计 使用和不使用介入性抗吸收药物的合成代谢药物给药方案，以实现 考虑患者的性别和性腺功能可获得最大的治疗收益。去卵巢(OVX)大鼠将被 用于模拟绝经后骨质疏松症和切除(ORX)大鼠将用于模拟 老年男性性腺功能减退。年龄匹配的完好无损的雄性和雌性大鼠将被用作青壮年， 性腺功能。我们假设骨骼对合成代谢治疗的反应是停止和循环的 给药方案受性激素和性激素的影响。在目标1中，我们将阐明 性激素和性激素对MBF动态反应的细胞机制的影响 停止RBF至合成代谢治疗。在目标2中，我们将优化循环给药方案 含和不含介入性抗吸收药的合成代谢药均可达到最佳治疗效果 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发育和保留的影响 考虑患者性别和性腺功能的骨质疏松症长期临床护理。

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.