破骨细胞
组织蛋白酶K
骨质疏松症
骨吸收
基因沉默
癌症研究
骨重建
医学
骨溶解
遗传增强
内科学
细胞生物学
内分泌学
化学
生物
受体
外科
基因
生物化学
作者
Yujing Yang,Jun Xie,Sachin Chaugule,Dan Wang,Jungmin Kim,JiHea Kim,Phillip W. L. Tai,Seok Kyo Seo,Ellen M. Gravallese,Guangping Gao,Jae-Hyuck Shim
标识
DOI:10.1016/j.omtm.2020.04.010
摘要
Improper activity of bone-resorbing osteoclasts results in low bone density and deterioration of bone structure, which increase the risk of fractures. Anti-resorptive therapies targeting osteoclasts have proven effective in preserving bone mass, but these therapeutic agents lead to defective new bone formation and numerous potential side effects. In this study, we demonstrate that recombinant adeno-associated virus, serotype 9 (rAAV9) can deliver to osteoclasts an artificial microRNA (amiR) that silences expression of key osteoclast regulators, RANK (receptor activator for nuclear factor κB) and cathepsin K (rAAV9.amiR-rank, rAAV9.amiR-ctsk), to prevent bone loss in osteoporosis. As rAAV9 is highly effective for the transduction of osteoclasts, systemic administration of rAAV9 carrying amiR-rank or amiR-ctsk results in a significant increase of bone mass in mice. Furthermore, the bone-targeting peptide motif (Asp)14 or (AspSerSer)6 was grafted onto the AAV9-VP2 capsid protein, resulting in significant reduction of transgene expression in non-bone peripheral organs. Finally, systemic delivery of bone-targeting rAAV9.amiR-ctsk counteracts bone loss and improves bone mechanical properties in mouse models of postmenopausal and senile osteoporosis. Collectively, inhibition of osteoclast-mediated bone resorption via bone-targeting rAAV9-mediated silencing of ctsk is a promising gene therapy that can preserve bone formation and mitigate osteoporosis, while limiting adverse off-target effects.
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