Zhang Wei, Zhou Xingzhi, Hou Weiduo, Chen Erman, Ye Chenyi, Chen Mo, Lu Qian, Yu Xiaohua, Li Weixu
Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, 310009, Hangzhou, China.
Research Institute of Orthopaedics, Zhejiang University, 310009, Hangzhou, China.
Bioact Mater. 2022 May 2;19:429-443. doi: 10.1016/j.bioactmat.2022.04.017. eCollection 2023 Jan.
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.) . 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.
骨稳态失衡是骨质疏松症的根本原因。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上，这些方法往往无法扭转失衡的骨代谢。在此，我们报道了一种SIRT-1激动剂介导的分子治疗策略，通过从矿物包被的无细胞基质微粒中局部持续释放SRT2104，同时调节成骨和破骨细胞生成，从而逆转骨稳态失衡。利用静电相互作用将SRT2104固定在矿物包被上（MAM/SRT），可使SIRT-1激动剂持续释放超过30天。MAM/SRT不仅增强了成骨细胞分化和矿化，还通过整合多个重要的上游信号（β-连环蛋白、FoxOs、Runx2、NFATc1等）减弱了过度破骨细胞的形成和功能。骨质疏松动物模型也证实，它加速了骨质疏松性骨愈合，并改善了周围骨的骨整合。总体而言，我们的工作提出了一种有前景的策略，即通过使用特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。
