AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy
John, Aijaz Ahmad ; Xie, Jun ; Yang, Yeon-Suk ; Kim, Jung-Min ; Lin, Chujiao ; Ma, Hong ; Gao, Guangping ; Shim, Jae-Hyuck
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Abstract
Osteoporosis occurs due to a dysregulation in bone remodeling, a process requiring both bone-forming osteoblasts and bone-resorbing osteoclasts. Current leading osteoporosis therapies suppress osteoclast-mediated bone resorption but show limited therapeutic effects because osteoblast-mediated bone formation decreases concurrently. We developed a gene therapy strategy for osteoporosis that simultaneously promotes bone formation and suppresses bone resorption by targeting two microRNAs (miRNAs)-miR-214-3p and miR-34a-5p. We modulated the expression of these miRNAs using systemically delivered recombinant adeno-associated viral (rAAV) vectors targeting the bone. rAAV-mediated overexpression of miR-214-3p or inhibition of miR-34a-5p in the skeleton resulted in bone loss in adult mice, resembling osteoporotic bones. Conversely, rAAV-mediated inhibition of miR-214-3p or overexpression of miR-34a-5p reversed bone loss in mouse models for postmenopausal and senile osteoporosis by increasing osteoblast-mediated bone formation and decreasing osteoclast-mediated bone resorption. Notably, these mice did not show any apparent pathological phenotypes in non-skeletal tissues. Mechanistically, inhibiting miR-214-3p upregulated activating transcription factor 4 in osteoblasts and phatase and tensin homolog in osteoclasts, while overexpressing miR-34a-5p downregulated Notch1 in osteoblasts and TGF-β-induced factor homeobox 2 in osteoclasts. In summary, bone-targeting rAAV-mediated regulation of miR-214-3p or miR-34a-5p is a promising new approach to treat osteoporosis, while limiting adverse effects in non-skeletal tissues.
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John AA, Xie J, Yang YS, Kim JM, Lin C, Ma H, Gao G, Shim JH. AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy. Mol Ther Nucleic Acids. 2022 Jul 11;29:296-311. doi: 10.1016/j.omtn.2022.07.008. PMID: 35950212; PMCID: PMC9352805.