Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degeneration

Nakamura, Akihiro; Rampersaud, Y. Raja; Sharma, Anjali; Lewis, Stephen J.; Wu, Bangbiao; Datta, P.; Sundararajan, Kala; Endisha, Helal; Rossomacha, Evgeny; Rockel, Jason S.; Jurišica, Igor; Kapoor, Mohit

doi:10.1172/jci.insight.86820

Cited by 64 publications

(55 citation statements)

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“…Current version of pathDIP has been already applied (32,33), highlighting the value of predicted pathway associations in pathway enrichment analysis. Furthermore, improved overlap of extended pathways compared with overlap of their core versions (Supplementary Figures S6 and S7) suggests that extended source-specific, same-class pathways converge to similar definitions, highlighting that pathDIP will contribute to consolidation of existing pathways.…”

Section: Future Workmentioning

confidence: 99%

pathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis

et al. 2016

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Molecular pathway data are essential in current computational and systems biology research. While there are many primary and integrated pathway databases, several challenges remain, including low proteome coverage (57%), low overlap across different databases, unavailability of direct information about underlying physical connectivity of pathway members, and high fraction of protein-coding genes without any pathway annotations, i.e. ‘pathway orphans’. In order to address all these challenges, we developed pathDIP, which integrates data from 20 source pathway databases, ‘core pathways’, with physical protein–protein interactions to predict biologically relevant protein–pathway associations, referred to as ‘extended pathways’. Cross-validation determined 71% recovery rate of our predictions. Data integration and predictions increase coverage of pathway annotations for protein-coding genes to 86%, and provide novel annotations for 5732 pathway orphans. PathDIP (http://ophid.utoronto.ca/pathdip) annotates 17 070 protein-coding genes with 4678 pathways, and provides multiple query, analysis and output options.

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Section: Future Workmentioning

confidence: 99%

pathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis

et al. 2016

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“…Literature has reported that alterations in non-coding genes can contribute to OA pathogenesis [9]. Synovial fluid microRNA signature is correlated with knee osteoarthritis stage, and microRNA-181a-5p and microRNA-4454 are known mediators of facet cartilage degeneration [10, 11]. In addition, recent evidence has shown that miR-27b and lncRNA-CIR contribute to ECM degradation and have key roles in the pathogenesis of OA[2, 6].…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNA CIR Promotes Chondrocyte Extracellular Matrix Degradation in Osteoarthritis by Acting as a Sponge For Mir-27b

Li¹,

Li²,

Liu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation. The degradation of the extracellular matrix (ECM) of chondrocyte is closely associated with the destruction of joints in OA patients. lncRNAs are non-coding segments of RNA that possess important regulatory functions at the cellular level and in a variety of pathophysiological processes. The present study was conducted to investigate whether lncRNA-CIR regulated the expression of MMP13 as a sponge of miR-27 in OA. Methods: Primary cultured chondrocytes were challenged by IL-1β and TNF-α to simulate OA conditions. qRT-PCR was performed to detect the miR-27, lncRNA-CIR, MMP13 mRNA expression levels. Western blot was applied to detect MMP13 protein expression. Soluble sGAG secretion/ formation was analysed by the dimethylmethylene blue (DMMB) assay. lncRNA-CIR overexpression or inhibition was performed using overexpression plasmid and small interfering RNAs (siRNAs), respectively. Results: lncRNA-CIR significantly up-regulated in OA patients, concomitantly down-regulated miR-27 and up-regulated MMP13. Bioinformatics analysis predicted miR-27 was the target of both lncRNA-CIR and MMP13. Overexpression of lncRNA-CIR significantly increased the expression of MMP13, while miR-27 remarkably suppressed the expression of MMP13, Accompanying with the increases of mRNA level, protein level and relative luciferase activity. Conclusion: The present findings indicated that lncRNA-CIR/miR-27/MMP13 axis involved in the degradation of the ECM of chondrocyte in OA.

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“…172 Increased levels of miR-181a was found in OA facet joint cartilage while decreased levels were identified in knee OA cartilage. 138,139 This again points to the possibility that miRNAs may have distinct functions in chondrocytes at different anatomical locations. Overexpression of miR-181a appears to be deleterious for facet cartilage, 138 yet whether or not the same is true for articular cartilage of the knee or hip remains to be determined.…”

Section: Mirnas Associated With Skeletal Disease and Other Orthopaedimentioning

confidence: 95%

“…With respect to chondrocyte homeostasis, miR-181a/b has been shown to decrease expression of aggrecan and CCN1 135 while in other studies it was reported to promote chondrocyte catabolism and apoptosis. [136][137][138] Nakamura et al found higher levels of miR-181a in OA facet joint cartilage compared to control specimens and showed that injection of miR-181a mimics into the facet joints of rats induced cartilage degradation. 138 Song et al reported higher levels of miR-181b in mouse OA articular cartilage (induced by joint destabilization surgery) and that inhibition of miR-181b by intraarticular injection of miR-181b antagomirs following surgery apparently attenuated the effects of OA.…”

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confidence: 99%

“…[136][137][138] Nakamura et al found higher levels of miR-181a in OA facet joint cartilage compared to control specimens and showed that injection of miR-181a mimics into the facet joints of rats induced cartilage degradation. 138 Song et al reported higher levels of miR-181b in mouse OA articular cartilage (induced by joint destabilization surgery) and that inhibition of miR-181b by intraarticular injection of miR-181b antagomirs following surgery apparently attenuated the effects of OA. 137 However, Tu et al reported decreased levels of the miR-181 family (miR-181a/b/c/d) in human OA articular cartilage tissue.…”

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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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Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degeneration

Cited by 64 publications

References 33 publications

pathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis

pathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis

Long Noncoding RNA CIR Promotes Chondrocyte Extracellular Matrix Degradation in Osteoarthritis by Acting as a Sponge For Mir-27b

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

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