PDF(Pubmed)
Abstract：
The imbalance of bone homeostasis is the root cause of osteoporosis. However current therapeutic approaches mainly focus on either anabolic or catabolic pathways, which often fail to turn the imbalanced bone metabolism around. Herein we reported that a SIRT-1 agonist mediated molecular therapeutic strategy to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis via locally sustained release of SRT2104 from mineral coated acellular matrix microparticles. Immobilization of SRT2104 on mineral coating (MAM/SRT) harnessing their electrostatic interactions resulted in sustained release of SIRT-1 agonist for over 30 days. MAM/SRT not only enhanced osteogenic differentiation and mineralization, but also attenuated the formation and function of excessive osteoclasts via integrating multiple vital upstream signals (β-catenin, FoxOs, Runx2, NFATc1, etc.) in vitro. Osteoporosis animal model also validated that it accelerated osteoporotic bone healing and improved osseointegration of the surrounding bone. Overall, our work proposes a promising strategy to treat osteoporotic bone defects by reversing the imbalance in bone homeostasis using designated small molecule drug delivery systems.
摘要：
骨稳态失衡是骨质疏松的根本原因。然而，目前的治疗方法主要集中在合成代谢或分解代谢途径，通常无法扭转不平衡的骨骼代谢。在本文中，我们报道了SIRT-1激动剂介导的分子治疗策略，通过从矿物质包被的无细胞基质微粒局部持续释放SRT2104同时调节成骨和破骨细胞生成来逆转骨稳态失衡。利用其静电相互作用将SRT2104固定在矿物涂层（MAM/SRT）上，导致SIRT-1激动剂持续释放30天以上。MAM/SRT不只加强成骨分化和矿化，而且还通过整合多个重要的上游信号（β-catenin，FoxOs,Runx2、NFATc1等。)在体外。骨质疏松动物模型还验证了其加速骨质疏松性骨愈合并改善周围骨的骨整合。总的来说,我们的工作提出了一个有前景的策略，通过使用指定的小分子药物递送系统逆转骨稳态失衡来治疗骨质疏松性骨缺损。
