Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity

Sun, Weijia; Zhao, Chenyang; Li, Yuheng; Wang, Liang; Nie, Guangjun; Jiang, Peng; Wang, Aiyuan; Zhang, Pengfei; Tian, Weiming; Li, Qi; Song, Jinping; Wang, Cheng; Xu, Xiaolong; Tian, Yanhua; Zhao, Di; Xu, Zi; Zhong, Guangming; Han, Bingxing; Ling, Shukuan; Chang, Yan; Li, Yingxian

doi:10.1038/celldisc.2016.15

Cited by 255 publications

(273 citation statements)

References 68 publications

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“…In another aspect, osteoclasts could also secret exosomes to modulate osteoblast function. Sun et al provided evidences and testified that osteoclasts secreted circulating miR-214 to inhibit osteoblast activity[18]. In agreement with the above findings, we showed that osteoblasts harbored high level of miR-433-3p (Fig 3) which might secret to circulating or tissue space.…”

Section: Discussionsupporting

confidence: 90%

MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression

et al. 2017

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Dickkopf-1 (DKK1) is a powerful antagonist of canonical WNT signaling pathway, and is regarded as a biomarker for osteoporosis. Its expression is highly correlated with bone mass and osteoblasts maturation. In this study, mouse primary bone marrow cells and osteoblast cell lines were used. Luciferase reporter assay and western blotting methods were employed to validate if miRNA-433-3p epigenetically regulated DKK1 translation. Rat bone marrow derived osteoblasts were infected with lentivirus vector in which miR-433-3p was constructed. The authors constructed lentivirus mediated miRNA-433-3p stable expression and examined the alkaline phosphatase (ALP) activity and mineral deposition level in vitro. In situ hybridization method was used to observe miR-433-3p in primary osteoblasts. We built up an OVX rat model to mimic postmenopausal osteoporosis, and found aberrant circulating miR-433-3p and miR-106b, which were not reported previously. Results showed that miR-433-3p potentially regulated DKK1 mRNA, Furthermore, the correlation of serum DKK1 with circulating miR-433-3p level was significant (r = 0.7520, p = 0.046). In the luciferase reporter assay, we found that miR-433-3p siRNA decreased luminescence signal, indicating direct regulation of miR-433-3p on DKK1 mRNA. When the miR-433-3p binding site in DKK1 3’UTR was mutant, such reduction was prohibited. Western blotting result validated that miR-433-3p inhibited over 90% of DKK1 protein expression. Similarly, the change of protein expression was not observed in mutant group. The stable expression of lentivirus mediated miR-433-3p increased ALP activity and mineralization both in human and rat derived immortalized cells. We found that primary osteoblasts had higher miR-433-3p level compared with immortal cells through real-time PCR, as well as in situ hybridization experiment. Conclusively, our findings further emphasized the vital role of miR-433-3p in DKK1/WNT/β-catenin pathway through decreasing DKK1 expression and inducing osteoblasts differentiation.

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Section: Discussionsupporting

confidence: 90%

MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression

et al. 2017

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“…Finally, they showed that the inhibition of osteoclastic-specific miR-214-3P enhanced bone formation in aging OVX mice. A recent study also showed that osteoclasts produced miRNA-enriched exosomes, and the exosomes transferred miR-214 into the osteoblasts to inhibit their activity (Sun et al, 2016). Osteoblast activity was inhibited in osteoclast-specific miR-214 transgenic mice.…”

Section: The Role Of Osteoclast In Bone Formationmentioning

confidence: 99%

Osteoblast–osteoclast interactions

Chen

Wang

Duan

et al. 2017

Connective Tissue Research

678

493

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Bone homeostasis depends on the resorption of bone by osteoclasts and formation of bone by osteoblasts. Imbalance of this tightly coupled process can cause diseases such as osteoporosis. Thus, the mechanisms that regulate communication between osteoclasts and osteoblasts are critical to bone cell biology. It has been shown that osteoblasts and osteoclasts can communicate with each other through direct cell-cell contact, cytokines and extracellular matrix interaction. Osteoblasts can affect osteoclast formation, differentiation or apoptosis through several pathways, such as OPG/RANKL/RANK, LGR4/RANKL/RANK, Ephrin2/ephB4 and Fas/FasL pathways. Conversely, osteoclasts also influence formation of bone by osteoblasts via the d2 isoform of vacuolar (H+) ATPase (v-ATPase) V0 domain (Atp6v0d2), complement component 3a, semaphorin 4D or microRNAs. In addition, cytokine released from the resorbed bone matrix, such as TGF-β and IGF-1 also affects the activity of osteoblasts. Several reviews have been performed on the osteoblasts-osteoclasts communication. However, few reviews have shown the research advances in the recent years. In this review we summarized the current knowledge on osteoblast-osteoclast communication.

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“…110 These antagomirs could also attenuate bone loss in aged OVX mice as well. A particularly exciting finding from this work, and another recent study 111 was that osteoclast-derived exosomes enriched in miR-214 could apparently be transferred to osteoblasts to inhibit bone formation. This data proposes the existence of miRNA-mediated cross-talk between osteoclasts and osteoblasts via exosomes to control bone homeostasis.…”

Section: Other Functional Mirnas With Therapeutic Potential To Treat mentioning

confidence: 59%

MicroRNAs in orthopaedic research: Disease associations, potential therapeutic applications, and perspectives

McAlinden

2017

Journal Orthopaedic Research

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MicroRNAs (miRNAs) are small non-coding RNAs that function to control many cellular processes by their ability to suppress expression of specific target genes. Tens to hundreds of target genes may be affected by one miRNA, thereby resulting in modulation of multiple pathways in any given cell type. Therefore, altered expression of miRNAs (i.e., during tissue development or in scenarios of disease or cellular stress) can have a profound impact on processes regulating cell differentiation, metabolism, proliferation, or apoptosis, for example. Over the past 5-10 years, thousands of reports have been published on miRNAs in cartilage and bone biology or disease, thus highlighting the significance of these non-coding RNAs in regulating skeletal development and homeostasis. For the purpose of this review, we will focus on miRNAs or miRNA families that have demonstrated function in vivo within the context of cartilage, bone or other orthopaedicrelated tissues (excluding muscle). Specifically, we will discuss studies that have utilized miRNA transgenic mouse models or in vivo approaches to target a miRNA with the aim of altering conditions such as osteoarthritis, osteoporosis and bone fractures in rodents. We will not discuss miRNAs in the context skeletal cancers since this topic is worthy of a review of its own. Overall, we aim to provide a comprehensive description of where the field currently stands with respect to the therapeutic potential of specific miRNAs to treat orthopaedic conditions and current technologies to target and modify miRNA function in vivo. KeywordsMicroRNAs (miRNAs); cartilage; bone; skeletal development; osteoarthritis MicroRNA (miRNAs) are small non-coding RNA molecules (typically 19-24 nucleotides in length) that function in RNA silencing and post-transcriptional regulation (suppression) of gene expression. 1 While the majority of miRNAs are located within the cell, some miRNAs, commonly known as circulating miRNA or extracellular miRNA, have also been detected outside the cell in the extracellular matrix, in various biological fluids, or in cell culture. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript miRNAs were first discovered over 20 years ago in the nematode Caenorhabditis elegans with the identification of the developmental regulator lin-4. 3 Since then, thousands of miRNAs have been identified and investigated, with a wide distribution in animals, plants, and viruses. 4 MicroRNAs are ubiquitously expressed in different organisms, and many of them are phylogenetically conserved. 5 To date, over 28,000 miR-NAs from various species are listed in the miRBase website (http://www.mirbase.org). Specifically, 2,588 mature miRNAs have been identified in humans and 1,915 mature miRNAs have been reported in mice.With respect to miRNA biosynthesis, transcription of miRNA genes that are located either intergenically or intragenically is mediated primarily by RNA polymerase II in eukaryotes, although RNA polymerase III has also been shown to transcrib...

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Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity

Cited by 255 publications

References 68 publications

MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression

MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression

Osteoblast–osteoclast interactions

MicroRNAs in orthopaedic research: Disease associations, potential therapeutic applications, and perspectives

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