biostudies-literature00470Yang YSNIAID NIH HHSNINDS NIH HHSNIAMS NIH HHS922-935https://www.ebi.ac.uk/biostudies/studies/S-EPMC7210389biostudies-literatureUnknown17Improper 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.<i>amiR-rank</i>, rAAV9.<i>amiR-ctsk</i>), to prevent bone loss in osteoporosis. As rAAV9 is highly effective for the transduction of osteoclasts, systemic administration of rAAV9 carrying <i>amiR-rank</i> or <i>amiR-ctsk</i> 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.<i>amiR-ctsk</i> 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 <i>ctsk</i> is a promising gene therapy that can preserve bone formation and mitigate osteoporosis, while limiting adverse off-target effects.Molecular therapy. Methods & clinical developmentBone-Targeting AAV-Mediated Gene Silencing in Osteoclasts for Osteoporosis Therapy.PMC7210389R21 AR072836R21 AR073331P01 AI100263R01 NS076991R01 AR068983P30 AR066261Kim JMShim JHChaugule SGravallese EYang YSXie JWang DTai PWLGao GKim JSeo SK47falseBone-Targeting AAV-Mediated Gene Silencing in Osteoclasts for Osteoporosis Therapy.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.<i>amiR-rank</i>, rAAV9.<i>amiR-ctsk</i>), to prevent bone loss in osteoporosis. As rAAV9 is highly effective for the transduction of osteoclasts, systemic administration of rAAV9 carrying <i>amiR-rank</i> or <i>amiR-ctsk</i> 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.<i>amiR-ctsk</i> 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 <i>ctsk</i> is a promising gene therapy that can preserve bone formation and mitigate osteoporosis, while limiting adverse off-target effects.2020-01-01T00:00:00Z2020 Jun2022-02-09T16:38:51.258Z2020-05-22T20:12:47ZS-EPMC72103893240551410.1016/j.omtm.2020.04.010