| First Author | Shen G | Year | 2020 |
| Journal | Theranostics | Volume | 10 |
| Issue | 10 | Pages | 4334-4348 |
| PubMed ID | 32292498 | Mgi Jnum | J:302408 |
| Mgi Id | MGI:6508257 | Doi | 10.7150/thno.42982 |
| Citation | Shen G, et al. (2020) miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss. Theranostics 10(10):4334-4348 |
| abstractText | 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 kappaB (NF-kappaB) activity by decreasing the level of acetylation of Lysine 310, as well as inhibiting tumor necrosis factor-alpha (Tnf-alpha) 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-kappaB signaling axis, highlighting a possible avenue for the further exploration of diagnostic and therapeutic target molecules in PMOP. |
