MiR-146a Deletion Protects From Bone Loss in OVX Mice by Suppressing RANKL/OPG and M-CSF in Bone Microenvironment

Abstract

MicroRNAs play important roles in osteoporosis and show great potential for diagnosis and therapy of osteoporosis. Previous studies have demonstrated that miR‐146a affects osteoblast (OB) and osteoclast (OC) formation. However, these findings have yet to be identified in vivo, and it is unclear whether miR‐146a is related to postmenopausal osteoporosis. Here, we demonstrated that miR‐146a knockout protects bone loss in mouse model of estrogen‐deficient osteoporosis, and miR‐146a inhibits OB and OC activities in vitro and in vivo. MiR‐146a−/− mice displayed the same bone mass as the wild type (WT) but exhibited a stronger bone turnover than the WT did under normal conditions. Nevertheless, miR‐146a−/− mice showed an increase in bone mass after undergoing ovariectomy (OVX) compared with those subjected to sham operation. OC activities were impaired in the miR‐146a−/− mice exposed to estrogen deficiency, which was diametrically opposite to the enhanced bone resorption ability of WT. Macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) from a bone microenvironment affect this extraordinary phenomenon. Therefore, our results implicate that miR‐146a plays a key role in estrogen deficiency–induced osteoporosis, and the inhibition of this molecule provides skeleton protection. © 2019 American Society for Bone and Mineral Research.

MiR-146a controls age related bone loss

“…In line with increased activity of Wnt proteins, we detected even decreasing bone marrow adiposity and increasing numbers of osteoblasts over time in miR-146a deficient mice. In addition, miR-146a deficient mice are, in accordance with a recent report [46], protected from OVX-induced bone loss. Interestingly, also during ovariectomy, we detected increased osteoblast and reduced generation of adipocytes in miR-146a deficient mice.…”

Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

“…Among the 384 microRNAs contained in the card, we identified 164 miRNAs in EVs from the MM1.S cell line and we then selected the most enriched ones based on their expression level (Ct <31, 2ˆ∆Ct ≥0.002). Out of forty enriched miRNAs, seven of them have been previously correlated with osteogenesis regulation (hsa-miR-34a [35][36][37], hsa-miR-30c [26,38], hsa-miR-127-5p [39,40], hsa-miR-106a [41], hsa-miR-188-3p [37], hsa-miR-129-5p [42][43][44][45], hsa-miR-146a [46,47] (Figure 2) Among those, we decided to focus our attention on hsa-miR-30c, hsa-miR-127-5p, hsa-miR-129-5p, and hsa-miR-146a since their validated and predicted targets are osteoblast differentiation markers. The presence of the four selected miRNAs in MM EVs was further confirmed by qRT-PCR in MM1.S and RPMI 8226 EVs as well as in the respective producing cell lines ( Figure 3A).…”

Identification of the Key Molecular Drivers of Phosphorus Utilization Based on Host miRNA-mRNA and Gut Microbiome Interactions

“…The current study shows the role of miRNAs in linking transcripts enriched in bone metabolism and immune functions. Many miRNAs are known to regulate bone metabolism, host-microbiome interaction, and inflammatory and immune processes [16,28,29]. MiR-146a affects osteoblast and osteoclast formation in vitro and in vivo miR-146a+/− mice [16,30].…”

“…Many miRNAs are known to regulate bone metabolism, host-microbiome interaction, and inflammatory and immune processes [16,28,29]. MiR-146a affects osteoblast and osteoclast formation in vitro and in vivo miR-146a+/− mice [16,30]. Using computational analysis and an in vitro cell culture system, miR-146b levels were shown to be significantly associated with chronic kidney disease and mineral bone disorder [31].…”

“…MiRNAs also play important roles in bone metabolism, bone-related diseases, and bone cell development and function [13][14][15][16]. Previous studies demonstrated that mRNA-miRNA regulatory networks affect different phenotypes, including endometrial receptivity in cattle, divergent muscle properties such as muscle fiber type, metabolic enzyme activity, and ATP production both in vivo pigs and in vitro in cell culture [17][18][19].…”