Regulation of microRNA‐221, ‐222, ‐21 and ‐27 in articular cartilage subjected to abnormal compressive forces

Stadnik, Paulina; Gilbert, Sophie; Tarn, Jessica; Charlton, Sarah; Skelton, Andrew; Barter, M.J.; Duance, Victor Colin; Young, David A.; Blain, Emma Jane

doi:10.1113/jp279810

Cited by 14 publications

(14 citation statements)

References 46 publications

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“…Preceding results showed EVs secreted by chondrocytes contained miR-221-3p, the expression level was consistent with the maternal cells [48] and it changed with mechanical loading [16,30]. To simulate the interface between cartilage and bone, and to evaluate how the miR-221-3p secreted by chondrocytes can potentially affect the bone formation capacity of osteoblasts, we cocultured these two cells in an in vitro model and found that the signal of overexpressed miR-221-3p in chondrocytes was transferred to osteoblasts with inhibited osteogenic markers expression of COL1A1 and RUNX2 (Figure 6a-b), while the OCN (Figure 6c), a late marker for bone formation [49], was not inhibited.…”

Section: Discussionmentioning

confidence: 69%

“…However, these studies have exclusively focused on the role of EVs on cartilage, despite the significance of the adjacent subchondral bone in the context of osteoarthritis [24]. Experimental evidence showed the mechanosensitive nature of miR-221 [16,29,30] and a paracrine effect from chondrocyte to chondrocyte [8] acting mainly on proliferation inside the same tissue. In this study, we demonstrate that chondrocyte derived EVs can inhibit the function of a completely different cell type (osteoblast) in a different tissue (bone), thereby establishing trans-tissue communication.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Vesicles Allow Epigenetic Mechanotransduction between Chondrocytes and Osteoblasts

Shang

Böker

Taheri

et al. 2021

IJMS

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MicroRNAs (miRNAs) can be transported in extracellular vesicles (EVs) and are qualified as possible messengers for cell–cell communication. In the context of osteoarthritis (OA), miR-221-3p has been shown to have a mechanosensitive and a paracrine function inside cartilage. However, the question remains if EVs with miR-221-3p can act as molecular mechanotransducers between cells of different tissues. Here, we studied the effect of EV-mediated transport in the communication between chondrocytes and osteoblasts in vitro in a rat model. In silico analysis (Targetscan, miRWalk, miRDB) revealed putative targets of miRNA-221-3p (CDKN1B/p27, TIMP-3, Tcf7l2/TCF4, ARNT). Indeed, transfection of miRNA-221-3p in chondrocytes and osteoblasts resulted in regulation of these targets. Coculture experiments of transfected chondrocytes with untransfected osteoblasts not only showed regulation of these target genes in osteoblasts but also inhibition of their bone formation capacity. Direct treatment with chondrocyte-derived EVs validated that chondrocyte-produced extracellular miR-221-3p was responsible for this effect. Altogether, our study provides a novel perspective on a possible communication pathway of a mechanically induced epigenetic signal through EVs. This may be important for processes at the interface of bone and cartilage, such as OA development, physiologic joint homeostasis, growth or fracture healing, as well as for other tissue interfaces with differing biomechanical properties.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Allow Epigenetic Mechanotransduction between Chondrocytes and Osteoblasts

Shang

Böker

Taheri

et al. 2021

IJMS

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“…The described upregulation of GLI3 in OA cartilage with the here-observed negative correlation would indeed be in line with a potential beneficial role for miRNA-181a-5p in cartilage homeostasis. Finally, miR-221-5p, previously found to be upregulated in lesioned as compared to preserved OA cartilage [ 19 ], and now shown to have predictive potential for OA progression, was shown to be induced in response to mechanical loading of bovine and mouse cartilage [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating MicroRNAs Highly Correlate to Expression of Cartilage Genes Potentially Reflecting OA Susceptibility—Towards Identification of Applicable Early OA Biomarkers

et al. 2021

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Objective: To identify and validate circulating micro RNAs (miRNAs) that mark gene expression changes in articular cartilage early in osteoarthritis (OA) pathophysiology process. Methods: Within the ongoing RAAK study, human preserved OA cartilage and plasma (N = 22 paired samples) was collected for RNA sequencing (respectively mRNA and miRNA). Spearman correlation was determined for 114 cartilage genes consistently and significantly differentially expressed early in osteoarthritis and 384 plasma miRNAs. Subsequently, the minimal number of circulating miRNAs serving to discriminate between progressors and non-progressors was assessed by regression analysis and area under receiver operating curves (AUC) was calculated with progression data and plasma miRNA sequencing from the GARP study (N = 71). Results: We identified strong correlations (ρ ≥ |0.7|) among expression levels of 34 unique plasma miRNAs and 21 genes, including 4 genes that correlated with multiple miRNAs. The strongest correlation was between let-7d-5p and EGFLAM (ρ = −0.75, P = 6.9 × 10−5). Regression analysis of the 34 miRNAs resulted in a set of 7 miRNAs that, when applied to the GARP study, demonstrated clinically relevant predictive value with AUC > 0.8 for OA progression over 2 years and near-clinical value for progression over 5 years- (AUC = 0.8). Conclusions: We show that plasma miRNAs levels reflect gene expression levels in cartilage and can be exploited to represent ongoing pathophysiological processes in articular cartilage. We advocate that identified signature of 7 plasma miRNAs can contribute to direct further studies toward early biomarkers predictive for progression of osteoarthritis over 2 and 5 years.

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“…MicroRNAs (miRNAs/miRs) are small non-coding RNAs involved in a wide range of biological regulatory processes; a number of studies have shown that numerous miRNAs play important roles in mechanical regulation (14,17) Under microgravity, the mechanosensory miR-103 is upregulated and may inhibit bone formation by targeting runt-related transcription factor 2 (Runx2) during osteoblast differentiation (18). Coincidentally, miR-103 inhibits osteoblast proliferation and bone formation mainly by suppressing the expression of the calcium channel voltage-dependent L type a 1C subunit, which encodes Cav1.2 under reduced load conditions (19).…”

Section: Tail Suspension Delays Ectopic Ossification In Proteoglycan-induced Ankylosing Spondylitis In Mice Via Mir-103/dkk1mentioning

confidence: 99%

Tail suspension delays ectopic ossification in proteoglycan‑induced ankylosing spondylitis in mice via miR‑103/DKK1

Zhang

Zeng

et al. 2021

Exp Ther Med

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Ankylosing spondylitis (AS), characterized by inflammatory lesions and osteophyte formation, is a common immune rheumatic disease affecting the sacroiliac and axial joints. A high-intensity mechanical load is known to accelerate the heterotopic ossification associated with enthesitis in AS. Thus, the present study explored whether decreased mechanical load could delay the heterotopic ossification in AS. First, 24-week-old female BALB/c mice were induced with proteoglycan (PG) to establish an AS model. The AS-induced pathological and bone morphological changes of the sacroiliac joint were confirmed by hematoxylin and eosin staining and microCT analysis, respectively. Subsequently, the mice were treated with interventions of different mechanical loads. Using reverse transcription-quantitative PCR, it was revealed that expression levels of the osteogenesis-related genes bone morphogenetic protein-2, runt-related transcription factor 2 and osteocalcin were significantly reduced in sacroiliac bone tissue after intervention with a reduced mechanical load. The level of mechanosensory microRNA (miR)-103 increased in response to reduced mechanical loads. Consistently, in groups with reduced mechanical load, proteins with mechanical functions, including ρ-associated coiled-coil-containing protein kinase 1 (ROCK1), phosphorylated (p)-Erk1/2 and β-catenin, were reduced compared with the PG control. A dual-luciferase assay verified that miR-103 binds to the 3'-untranslated region end of Rock1 mRNA, thus negatively regulating the activity of Rock1 and affecting pathological ossification during AS. However, immunohistochemical staining indicated that the expression of dickkopf Wnt signaling pathway inhibitor 1, an inhibitor of the Wnt/β-catenin pathway, was increased in sacroiliac tissues. The results indicated that tail suspension decreased the mechanical load, thus reducing the bone formation in AS mice. Furthermore, tail suspension could inhibit the activation of mechanical kinase ROCK1 and p-Erk1/2 in the MAPK signaling pathway by upregulating miR-103, thereby inhibiting the classical osteogenesis-related Wnt/β-catenin pathway in AS. In summary, the present study uncovered the ameliorative effect of suspension on AS and its therapeutic potential for AS.

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Regulation of microRNA‐221, ‐222, ‐21 and ‐27 in articular cartilage subjected to abnormal compressive forces

Cited by 14 publications

References 46 publications

Extracellular Vesicles Allow Epigenetic Mechanotransduction between Chondrocytes and Osteoblasts

Extracellular Vesicles Allow Epigenetic Mechanotransduction between Chondrocytes and Osteoblasts

Circulating MicroRNAs Highly Correlate to Expression of Cartilage Genes Potentially Reflecting OA Susceptibility—Towards Identification of Applicable Early OA Biomarkers

Tail suspension delays ectopic ossification in proteoglycan‑induced ankylosing spondylitis in mice via miR‑103/DKK1

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