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Review
. 2017 Jun;20 Suppl 1(Suppl 1):95-99.
doi: 10.1111/ocr.12165.

Exosomes: novel regulators of bone remodelling and potential therapeutic agents for orthodontics

L S Holliday  1   2 , K P McHugh  3 , J Zuo  1 , J I Aguirre  4 , J K Neubert  1 , W J Rody Jr  1
Affiliations
Review

Exosomes: novel regulators of bone remodelling and potential therapeutic agents for orthodontics

L S Holliday et al. Orthod Craniofac Res. 2017 Jun.

Abstract

Recent studies suggest that exosomes are involved in intercellular communication required for the maintenance of healthy bone. Exosomes are small (30-150 nm in diameter) extracellular vesicles that are formed in multivesicular bodies and are released from cells as the multivesicular bodies fuse with the plasma membrane. Regulatory exosomes have the capacity to exert profound control over target cells. They can stimulate plasma membrane receptors and are also internalized by the target cell delivering proteins, lipids, small molecules and functional RNAs from the cell of origin. We and others have recently reported on regulatory exosomes from osteoclasts and osteoblasts. Key candidate molecules identified in exosome-based regulation of bone remodelling include receptor activator of nuclear factor kappa B (RANK), RANK-ligand (RANKL), ephrinA2, semaphorin 4D, microRNA-146a and microRNA- 214-3p. Exosomes will likely prove to be crucial elements in the communication networks integrating bone cells (osteoclasts, osteoblasts, osteocytes) and linking bone to other tissue. Exosomes collected from bone cells grown in culture may prove useful to augment bone remodelling associated with orthodontic force application or required for the repair of craniofacial bone. Various technologies allow exosomes to be engineered to improve their targeting and efficacy for therapeutic purposes. In summary, exosomes have emerged as important elements of the machinery for intercellular communication between bone cells. They hold great promise as therapeutic targets, biomarkers and therapeutic agents for orthodontists.

Keywords: RANK; extracellular vesicle; microvesicle; osteoblast; osteoclast.

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Figures

Figure 1
Figure 1. MicroRNA-146a and microRNA-214-3p are enriched in exosomes derived from osteoclasts compared with precursors
Total RNA was isolated from exosomes exactly as described in the protocol for the SeraMir Exosome RNA Purification Column Kit (System Biosciences). RNA was measured and assessed for quality using NanoDrop spectrophotometer. High-quality exosomal RNAs were analyzed by real-time quantitative PCR (qPCR). To determine mature miRNA expression, total RNAs were reverse-transcribed with High-Capacity cDNA Reverse Transcription Kit (Life Technologies) with a stem-loop RT primer designed based on the sequence of target genes (Applied Biosciences). Real-time PCR was performed using TaqMan® miRNA primers (Applied Biosciences) specific for miR-214-3p (002306) and miR-146a (000468) with a StepOnePlus Real-Time PCR System (Applied Biosystems). qRT-PCR were performed using an ABI Prism 7700 HT detection system (Applied Biosystems, Foster City, CA). Three biological replicates were used. In order to carry out absolute miRNA quantification, a serial dilution of a known concentration of appropriate miRNA mimics (Applied Biosciences) were used to plot standard curves and the number of miRNAs were determined as described. Data are presented as the relative number of microRNAs/unit of acetylcholinesterase activity (a quantitative marker of exosomes). The relative expression levels of the miRNAs were calculated using the 2−ΔΔCt method, values were analyzed by Student's t test with p< 0.05 considered significant. Asterisk indicates significantly different from precursor.
Figure 2
Figure 2. Regulation of osteoclastogenesis by exosomes released by osteoclasts
In C-SMM, exosomes isolated from osteoclast precursors increased the number of osteoclasts produced. In contrast, RANK-rich exosomes from inactive osteoclasts inhibited osteoclast formation in the same culture. This suggests that exosomes released by osteoclasts and their precursors provide bone cells with information regarding how many osteoclasts and precursors are present, which the bone cells use to produce a response to the calciotropic hormone. Currently we do not know the regulatory activity of exosomes from resorbing osteoclasts.
Figure 3
Figure 3. Exosomes enriched in RANKL and RANK increase the potential regulatory complexity of the RANKL-RANK-osteoprotegerin regulatory system
As shown in the schematic, new interactions between RANKL and RANK in exosomes produce new regulatory circuits and a means for extending the regulatory range of these molecules.
See this image and copyright information in PMC

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