老年妇女骨形成下降的分子机制研究：CKIP-1的功能性作用

Osteoporotic fractures seriously affect health in aged women. Intermittent Parathyroid Hormone (iPTH) is the exclusive bone anabolic agent clinically approved by FDA (USA) for reversing established osteoporosis. However, the dominantly increased bone resorption after 2-year-treatment with iPTH is a great concern. Thus, it is necessary to understand the pathophysiological mechanism of bone formation reduction in aged women. Casein kinase-2 interacting protein-1 (CKIP-1) is a newly discovered intracellular negative regulator of bone formation without activating bone resorption in bone physiology. The applicants further found that abnormally increased CKIP-1 in osteogenic cells was accompanied by decreased bone formation in aged females, implying the potential participation of CKIP-1 in pathophysiological mechanism of bone formation reduction in aged women. To test the hypothesis, the applicant's group has developed a targeted delivery system specifically approaching osteogenic cells and a cross-species CKIP-1 siRNA. In this proposal, the applicant will use the targeted delivery system to achieve osteogenic cell-specific gene silencing and thus examine the effect of the cross-species CKIP-1 siRNA encapsulated by the targeted delivery system on bone formation in aged rats with osteoporosis induced by ovariectomy. The potential findings would provide a bone anabolic strategy to treat bone formation reduction in aged women.

骨质疏松性骨折严重影响老年妇女的健康。PTH是目前唯一公认的能够逆转骨量丢失的促骨形成药物，但长期使用会造成骨吸收增加的风险，理解老年妇女骨形成下降的病理生理机制对于研发新的促骨形成药物非常重要。CKIP-1是新发现的在生理功能上具有抑制成骨细胞介导的骨形成但不影响骨吸收的细胞内调控因子。申请人进一步发现雌性个体在增龄过程中，骨形成的下降伴随骨(成骨细胞)内CKIP-1表达的上升，暗示成骨细胞内CKIP-1的高表达可能参与了老年妇女骨形成下降的病理生理机制。为了检验该假说，我们前期开发了一个特异性靶向成骨细胞的核酸递送系统以及筛选到了一个跨种属的CKIP-1核酸干扰序列。本研究以老年绝经后骨质疏松大鼠模型作为研究对象，拟结合上述递送系统与核酸干扰序列实现模型成骨细胞内CKIP-1的静默，定量观察对骨形成以及相关参数的影响，提供临床一个针对老年妇女骨形成下降具有转化潜能的成骨治疗策略。

骨质疏松性骨折严重影响老年妇女的健康。PTH是目前唯一公认的能够逆转骨量丢失的促骨形成药物，但长期使用会造成骨吸收增加的风险，理解老年妇女骨形成下降的病理生理机制对于研发新的促骨形成药物非常重要。CKIP-1是新发现的在生理功能上具有抑制成骨细胞介导的骨形成但不影响骨吸收的细胞内调控因子。本项研究以老年绝经后骨质疏松大鼠模型作为研究对象，拟结合上述递送系统与核酸干扰序列实现模型成骨细胞内CKIP-1 的静默，定量观察对骨形成以及相关参数的影响，提供临床一个针对老年妇女骨形成下降具有转化潜能的成骨治疗策略。 实验设计中以卵巢切除诱导的老年大鼠作为实验动物模型，通过静脉途径给予模型由靶向骨形成表面的递送系统(DSS)6-liposome 携带的CKIP-1 siRNA，进而从以下方面评价其靶向递送、细胞特异性静默、成骨效能及安全性。截至结题，项目组已验证了(DSS)6-liposome-CKIP-1siRNA在大鼠绝经后骨质疏松疾病模型中的治疗效果，为临床转化提供了依据。同时，阐明了CKIP-1在老年妇女骨形成下降病生机制中的功能性作用，为开发骨形成促进药物提供治疗靶点。