AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy.
AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy.
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DOI：
10.1016/j.omtn.2022.07.008
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发表时间：
2022-09-13
期刊：
影响因子：
--
通讯作者：
Shim, Jae-Hyuck
中科院分区：
文献类型：
--
作者：
John, Aijaz Ahmad;Xie, Jun;Yang, Yeon-Suk;Kim, Jung-Min;Lin, Chujiao;Ma, Hong;Gao, Guangping;Shim, Jae-Hyuck
骨质疏松症的发生是由于骨重建的失调，这个过程需要骨形成成骨细胞和骨吸收破骨细胞。目前主要的骨质疏松治疗方法抑制破骨细胞介导的骨吸收，但由于成骨细胞介导的骨形成同时减少，所以治疗效果有限。我们开发了一种针对骨质疏松症的基因治疗策略，通过靶向两个microRNAs(MiRNAs)-miR-214-3p和miR-34a-5p，同时促进骨形成和抑制骨吸收。我们使用系统递送的针对骨骼的重组腺相关病毒(RAAV)载体来调节这些miRNAs的表达。RAAV介导的miR-214-3p在骨骼中的过表达或miR-34a-5p的抑制导致成年小鼠的骨丢失，类似于骨质疏松。相反，rAAV介导的miR-214-3p的抑制或miR-34a-5p的过表达通过增加成骨细胞介导的骨形成和减少破骨细胞介导的骨吸收来逆转绝经后和老年性骨质疏松症小鼠模型中的骨丢失。值得注意的是，这些小鼠在非骨骼组织中没有表现出任何明显的病理表型。机制上，抑制miR-2 14-3p可上调成骨细胞中激活转录因子4和破骨细胞中的phatase和tensin同源物，而过表达miR-34a-5p则下调成骨细胞中的Notch1和转化生长因子β诱导的破骨细胞中的同源盒2。总之，骨靶向rAAV介导的miR-214-3p或miR-34a-5p的调节是一种很有前途的治疗骨质疏松症的新方法，同时限制了对非骨骼组织的不良反应。目前针对破骨细胞的抗吸收疗法已被证明对骨质疏松症有效，但由于同时减少骨形成，治疗效果有限。作者证明，AAV9介导的针对成骨细胞和破骨细胞的microRNAs(抗miR-214-3p或miR-34-5p)的调节可以抵消绝经后和老年性骨质疏松症小鼠模型的骨丢失。
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. Current anti-resorptive therapies targeting osteoclasts have proven effective for osteoporosis, but show limited therapeutic effects due to concurrent reduction of bone formation. The authors demonstrate that AAV9-mediated modulation of microRNAs, anti-miR-214-3p or miR-34-5p, in osteoblasts and osteoclasts can counteract bone loss in mouse models of postmenopausal and senile osteoporosis.
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破骨细胞来源的外泌体 miR-214-3p 抑制成骨细胞骨形成
影响因子：
16.6
作者：
Li D;Liu J;Guo B;Liang C;Dang L;Lu C;He X;Cheung HY;Xu L;Lu C;He B;Liu B;Shaikh AB;Li F;Wang L;Yang Z;Au DW;Peng S;Zhang Z;Zhang BT;Pan X;Qian A;Shang P;Xiao L;Jiang B;Wong CK;Xu J;Bian Z;Liang Z;Guo DA;Zhu H;Tan W;Lu A;Zhang G
通讯作者：
Zhang G
DOI：
10.1016/j.omtn.2017.06.005
发表时间：
2017-09-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Chakraborty C;Sharma AR;Sharma G;Doss CGP;Lee SS
通讯作者：
Lee SS
影响因子：
10.9
作者：
Hart, Martin;Walch-Rueckheim, Barbara;Meese, Eckart
通讯作者：
Meese, Eckart
影响因子：
64.5
作者：
Krol, Jacek;Busskamp, Volker;Filipowicz, Witold
通讯作者：
Filipowicz, Witold
影响因子：
9.2
作者：
Li Y;Xia M;Peng L;Liu H;Chen G;Wang C;Yuan D;Liu Y;Liu H
通讯作者：
Liu H