Inhibition of miR-29-3p isoforms via tough decoy suppresses osteoblast function in homeostasis but promotes intermittent parathyroid hormone-induced bone anabolism.
Inhibition of miR-29-3p isoforms via tough decoy suppresses osteoblast function in homeostasis but promotes intermittent parathyroid hormone-induced bone anabolism.
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通过坚韧诱饵抑制miR-29- 3 p亚型抑制成骨细胞的稳态功能，但促进间歇性甲状旁腺激素诱导的骨愈合
DOI：
10.1016/j.bone.2020.115779
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发表时间：
2021-03
期刊：
影响因子：
4.1
通讯作者：
Delany AM
中科院分区：
文献类型：
--
作者：
Hrdlicka HC;Pereira RC;Shin B;Yee SP;Deymier AC;Lee SK;Delany AM
miRNAs在成骨细胞和破骨细胞的基因表达的转录后调节中起着至关重要的作用，并且miR-29家族在这两种谱系中均表达。使用全球表达miR-29- 3 p坚韧诱饵的小鼠，我们证明了所有三种miR-29- 3 p亚型：miR-29 a，miR-29 b和miR-29 c的适度减少30-60%。虽然miR-29- 3 p诱饵不影响破骨细胞的数量或功能，但坚韧的诱饵减少了生长小鼠的骨形成，这导致成熟动物的骨小梁体积减少。这些数据支持了先前的体外研究，表明miR-29- 3 p是成骨细胞分化的正调控因子。相反，当小鼠接受间歇性甲状旁腺激素（PTH 1 -34）治疗时，抑制miR-29- 3 p增强了PTH对皮质骨的作用，增加了骨形成率和成骨细胞表面，并增加了Ctnnb 1/β连环蛋白mRNA（miR-29靶点）的水平。这些发现突出了控制基础水平骨形成和由间歇性PTH诱导的骨形成的机制的差异。总体而言，整体miR-29- 3 p坚韧诱饵模型代表了适度的功能丧失，这可能是评估全身施用miR-29- 3 p抑制剂的可能影响的相关工具。我们的研究为PTH 1 -34和miR-29- 3 p抑制剂的联合给药提供了潜在的理论基础，以促进严重骨质疏松症患者的骨形成，特别是在皮质区室中。
miRNAs play a vital role in post-transcriptional regulation of gene expression in osteoblasts and osteoclasts, and the miR-29 family is expressed in both lineages. Using mice globally expressing a miR-29-3p tough decoy, we demonstrated a modest 30–60% decrease all three miR-29-3p isoforms: miR-29a, miR-29b, and miR-29c. While the miR-29-3p decoy did not impact osteoclast number or function, the tough decoy decreased bone formation in growing mice, which led to decreased trabecular bone volume in mature animals. These data support previous in vitro studies suggesting that miR-29-3p is a positive regulator of osteoblast differentiation. In contrast, when mice were treated with intermittent parathyroid hormone (PTH1-34), inhibition of miR-29-3p augmented the effect of PTH on cortical bone anabolism, increased bone formation rate and osteoblast surface, and increased levels of Ctnnb1/βcatenin mRNA, which is a miR-29 target. These findings highlight differences in the mechanisms controlling basal level bone formation and bone formation induced by intermittent PTH. Overall, the global miR-29-3p tough decoy model represents a modest loss-of-function, which could be a relevant tool for assessing the possible impact of systemically administered miR-29-3p inhibitors. Our studies provide a potential rationale for co-administration of PTH1-34 and miR-29-3p inhibitors, to boost bone formation in severely affected osteoporosis patients, particularly in the cortical compartment.
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影响因子：
4.1
作者：
Hollensen, Anne Kruse;Bak, Rasmus O.;Mikkelsen, Jacob Giehm
通讯作者：
Mikkelsen, Jacob Giehm
Mirbase：MicroRNA基因组学的工具。
影响因子：
14.9
作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.
通过PTH受体下游的不同机制对机械负荷和PTH的响应控制骨变性。
DOI：
10.1002/jbmr.3011
发表时间：
2017-03
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Delgado-Calle J;Tu X;Pacheco-Costa R;McAndrews K;Edwards R;Pellegrini GG;Kuhlenschmidt K;Olivos N;Robling A;Peacock M;Plotkin LI;Bellido T
通讯作者：
Bellido T
影响因子：
14.9
作者：
Griffiths-Jones S;Grocock RJ;van Dongen S;Bateman A;Enright AJ
通讯作者：
Enright AJ
影响因子：
48
作者：
Ebert, Margaret S.;Neilson, Joel R.;Sharp, Phillip A.
通讯作者：
Sharp, Phillip A.