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miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss
Postmenopausal osteoporosis (PMOP) is a severe health issue faced by postmenopausal women. microRNA-128 (miR-128) is associated with aging, inflammatory signaling, and inflammatory diseases, such as PMOP. It has also been reported to modulate in vitro osteogenic/adipogenic differentiation. However,...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150474/ https://www.ncbi.nlm.nih.gov/pubmed/32292498 http://dx.doi.org/10.7150/thno.42982 |
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author | Shen, Gengyang Ren, Hui Shang, Qi Zhang, Zhida Zhao, Wenhua Yu, Xiang Tang, Jingjing Yang, Zhidong Liang, De Jiang, Xiaobing |
author_facet | Shen, Gengyang Ren, Hui Shang, Qi Zhang, Zhida Zhao, Wenhua Yu, Xiang Tang, Jingjing Yang, Zhidong Liang, De Jiang, Xiaobing |
author_sort | Shen, Gengyang |
collection | PubMed |
description | Postmenopausal osteoporosis (PMOP) is a severe health issue faced by postmenopausal women. microRNA-128 (miR-128) is associated with aging, inflammatory signaling, and inflammatory diseases, such as PMOP. It has also been reported to modulate in vitro osteogenic/adipogenic differentiation. However, its function in osteoclast formation is unknown. Methods: First, the expression of miR-128 and nuclear factor of activated T cells 1 (Nfatc1, bone resorption master marker) was investigated in bone tissues derived from PMOP patients, while their correlation to each other was also investigated. The levels of miR-128 and Nfatc1 in bone specimens and bone marrow-derived macrophages (BMMs) from mice subjected to ovariectomy (OVX) were also assayed. Next, we employed mice BMMs modified for overexpression and inhibition of miR-128 levels to determine its effect on osteoclast differentiation. Moreover, we generated osteoclastic miR-128 conditional knockout (miR-128(Oc-/-)) mice and isolated miR-128 deletion-BMMs to observe its biological function on bone phenotype and osteoclastogenesis in vivo, respectively. The miR-128(Oc-/-) BMMs were used to explore the downstream regulatory mechanisms using pull-down, luciferase reporter, and western-blotting assays. Finally, the impact of miR-128 deficiency on OVX-induced bone loss in mice was evaluated. Results: The miR-128 level was found to be positively correlated with the increase in Nfatc1 level in mouse/human bone specimens and mouse primary BMMs. In vitro experiments demonstrated miR-128 levels that were dependent on activity of osteoclast differentiation and miR-128 overexpression or inhibition in BMMs significantly increased or decreased osteoclastogenesis, respectively. In vivo, we revealed that osteoclastic miR-128 deletion remarkedly increased bone mass through the inhibition of osteoclastogenesis. Mechanistically, we identified sirtuin 1 (SIRT1) as the direct target of miR-128 at the post-transcriptional level during osteoclast differentiation. Increased levels of SIRT1 reduced nuclear factor κB (NF-κB) activity by decreasing the level of acetylation of Lysine 310, as well as inhibiting tumor necrosis factor-α (Tnf-α) and interleukin 1 (IL-1) expressions. Lastly, osteoclastic deletion of miR-128 significantly suppressed OVX-triggered osteoclastogenesis and exerted a protective effect against bone loss in mice. Conclusions: Our findings reveal a critical mechanism for osteoclastogenesis that is mediated by the miR-128/SIRT1/NF-κB signaling axis, highlighting a possible avenue for the further exploration of diagnostic and therapeutic target molecules in PMOP. |
format | Online Article Text |
id | pubmed-7150474 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-71504742020-04-14 miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss Shen, Gengyang Ren, Hui Shang, Qi Zhang, Zhida Zhao, Wenhua Yu, Xiang Tang, Jingjing Yang, Zhidong Liang, De Jiang, Xiaobing Theranostics Research Paper Postmenopausal osteoporosis (PMOP) is a severe health issue faced by postmenopausal women. microRNA-128 (miR-128) is associated with aging, inflammatory signaling, and inflammatory diseases, such as PMOP. It has also been reported to modulate in vitro osteogenic/adipogenic differentiation. However, its function in osteoclast formation is unknown. Methods: First, the expression of miR-128 and nuclear factor of activated T cells 1 (Nfatc1, bone resorption master marker) was investigated in bone tissues derived from PMOP patients, while their correlation to each other was also investigated. The levels of miR-128 and Nfatc1 in bone specimens and bone marrow-derived macrophages (BMMs) from mice subjected to ovariectomy (OVX) were also assayed. Next, we employed mice BMMs modified for overexpression and inhibition of miR-128 levels to determine its effect on osteoclast differentiation. Moreover, we generated osteoclastic miR-128 conditional knockout (miR-128(Oc-/-)) mice and isolated miR-128 deletion-BMMs to observe its biological function on bone phenotype and osteoclastogenesis in vivo, respectively. The miR-128(Oc-/-) BMMs were used to explore the downstream regulatory mechanisms using pull-down, luciferase reporter, and western-blotting assays. Finally, the impact of miR-128 deficiency on OVX-induced bone loss in mice was evaluated. Results: The miR-128 level was found to be positively correlated with the increase in Nfatc1 level in mouse/human bone specimens and mouse primary BMMs. In vitro experiments demonstrated miR-128 levels that were dependent on activity of osteoclast differentiation and miR-128 overexpression or inhibition in BMMs significantly increased or decreased osteoclastogenesis, respectively. In vivo, we revealed that osteoclastic miR-128 deletion remarkedly increased bone mass through the inhibition of osteoclastogenesis. Mechanistically, we identified sirtuin 1 (SIRT1) as the direct target of miR-128 at the post-transcriptional level during osteoclast differentiation. Increased levels of SIRT1 reduced nuclear factor κB (NF-κB) activity by decreasing the level of acetylation of Lysine 310, as well as inhibiting tumor necrosis factor-α (Tnf-α) and interleukin 1 (IL-1) expressions. Lastly, osteoclastic deletion of miR-128 significantly suppressed OVX-triggered osteoclastogenesis and exerted a protective effect against bone loss in mice. Conclusions: Our findings reveal a critical mechanism for osteoclastogenesis that is mediated by the miR-128/SIRT1/NF-κB signaling axis, highlighting a possible avenue for the further exploration of diagnostic and therapeutic target molecules in PMOP. Ivyspring International Publisher 2020-03-04 /pmc/articles/PMC7150474/ /pubmed/32292498 http://dx.doi.org/10.7150/thno.42982 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Shen, Gengyang Ren, Hui Shang, Qi Zhang, Zhida Zhao, Wenhua Yu, Xiang Tang, Jingjing Yang, Zhidong Liang, De Jiang, Xiaobing miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss |
title | miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss |
title_full | miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss |
title_fullStr | miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss |
title_full_unstemmed | miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss |
title_short | miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss |
title_sort | mir-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150474/ https://www.ncbi.nlm.nih.gov/pubmed/32292498 http://dx.doi.org/10.7150/thno.42982 |
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