MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

This study was aimed to explore the role of miR-29b-3p and PGRN in chondrocyte apoptosis and the initiation and progress of osteoarthritis (OA). Both miR-29b-3p and PGRN were up-regulated in cartilage tissue from patients with OA. Transfection of miR-29b-3p mimic into rat primary chondrocytes and SW1353 chondrosarcoma cells significantly suppressed PGRN expression and release, induced apoptosis, inhibited proliferation and scratch wound closure. By contrast, transfection of miR-29b-3p inhibitor exhibited the opposite effects. Moreover, the expression and secretion of cartilaginous degeneration-related molecules were also altered by miR-29b-3p. Luciferase reporter gene assay showed rat GRN mRNA is directly targeted and repressed by miR-29b-3p. The fact that recombinant PGRN or shPGRN-mediated PGRN interference abolished miR-29b-3p mimic-induced cell apoptosis and growth inhibition suggested miR-29b-3p affect the cellular functions of chondrocyte through regulating PGRN expression. In vivo, joint cavity injection of miR-29b-3p antagomir prior to surgical induction of OA significantly suppressed the upregulation of miR-29b-3p, whereas further promoted the increased expression of PGRN. Articular chondrocytes apoptosis and cartilage loss in the knee joint of surgically induced OA rats were also ameliorated by the injection of miR-29b-3p antagomir, demonstrated by TUNEL and safranin O-fast green staining. This work showed miR-29b-3p facilitates chondrocyte apoptosis and OA by targeting PGRN, and miR-29b-3p or PGRN may be the potential target for OA treatments.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.13237

MiR-29b-3p promotes chondrocyte apoptosis and facilitates the occurrence and development of osteoarthritis by targeting PGRN.

An imbalance in gene expressional events skewing chondrocyte anabolic and catabolic pathways toward the latter causes an aberrant turnover and loss of extracellular matrix proteins in osteoarthritic (OA) articular cartilage. Thus, catabolism results in the elevated loss of extracellular matrix proteins. There is also evidence of an increase in the frequency of chondrocyte apoptosis that compromises the capacity of articular cartilage to undergo repair. Although much of the fundamental OA studies over the past 20 years identified and characterized many genes relevant to pro-inflammatory cytokines, apoptosis, and matrix metalloproteinases (MMPs)/a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS), more recent studies focused on epigenetic mechanisms and the associated role of microRNAs (miRs) in regulating gene expression in OA cartilage. Thus, several miRs were identified as regulators of chondrocyte signaling pathways, apoptosis, and proteinase gene expression. For example, the reduced expression of miR-146a was found to be coupled to reduced type II collagen (COL2) in OA cartilage, whereas MMP-13 levels were increased, suggesting an association between MMP-13 gene expression and COL2A1 gene expression. Results of these studies imply that microRNAs could become useful in the search for diagnostic biomarkers, as well as providing novel therapeutic targets for intervention in OA.

https://www.mdpi.com/2073-4409/7/8/92/pdf

MicroRNAs and Osteoarthritis.

MicroRNAs are small double-stranded RNAs, which negatively regulate gene expression and have been shown to have key roles in both chondrocyte development and cartilage homeostasis with age. Deletion of all microRNAs in chondrocytes leads to skeletal growth defects in mice, whilst deletion of specific microRNAs, e.g. miR-140, leads to premature articular cartilage degradation and increased susceptibility to posttraumatic osteoarthritis. Studies comparing microRNA expression in normal human articular cartilage compared to osteoarthritic cartilage show differential expression, but varying sample groups make interpretation difficult. MicroRNAs have been proposed as circulating biomarkers of osteoarthritis, but again, this differs amongst patient cohorts. Many micro-RNAs have been shown to have roles in chondrocyte phenotype via signalling pathways, apoptosis, autophagy and senescence. Modulating microRNAs in the joint has been shown to reduce osteoarthritis in animal models and translating this to man as a novel therapeutic strategy will be key.

The function of microRNAs in cartilage and osteoarthritis.

Micro ribonucleic acid (microRNA) regulation and expression has become an emerging field in determining the mechanisms regulating a variety of inflammation-mediated diseases. Several studies have focused on specific microRNAs that are differentially expressed in cases of osteoarthritis. Furthermore, several targets of these miRNAs important in disease progression have also been identified. In this review, we focus on microRNA biogenesis, regulation, detection, and quantification with an emphasis on cellular localization and how these concepts may be linked to disease processes such as osteoarthritis. Next, we review the relationships of specific microRNAs to certain features and risk factors associated with osteoarthritis such as inflammation, obesity, autophagy, and cartilage homeostasis. We also identify certain microRNAs that are differentially expressed in osteoarthritis but have unidentified targets and functions in the disease state. Lastly, we identify the potential use of microRNAs for therapeutic purposes and also mention certain remedies that regulate microRNA expression.

/pdf/the-role-of-micrornas-and-their-targets-in-osteoarthritis-1s197r9t28.pdf

The Role of MicroRNAs and Their Targets in Osteoarthritis

MicroRNAs are short endogenous non-coding RNA molecules, typically 19-25 nucleotides in length, which negatively regulate gene expression. In osteoarthritis (OA), several genes necessary for cartilage homeostasis are aberrantly expressed, with a number of miRNAs implicated in this process. However, our knowledge of the earliest stages of OA, prior to the onset of irreversible changes, remains limited. The purpose of this study was to identify miRNAs involved across the time-course of OA using both a murine model and human cartilage, and to define their function.
Expression profile of miRNAs (Exiqon) and mRNAs (Illumina) on total RNA purified from whole knee joints taken from mice which underwent destabilisation of the medial meniscus (DMM) surgery at day 1, 3 and 7 post-surgery showed: the miRNA expression in whole mouse joints post DMM surgery increased over 7 days; at day 1 and 3, the expression of only 4 miRNAs altered significantly; at day 7, 19 miRNAs were upregulated and 15 downregulated. Among the modulated miRNAs, the miR-29b was the most interesting and was chosen to further investigate since integrating analysis of the miRNA and mRNA expression array data showed the inverse correlation between miR-29b and its
potential targets. In end-stage human OA cartilage and in murine injury model, the miR-29 family was found to increase expression. Moreover, the miR-29 family was found to be the negative regulator in both human and murine chondrogenesis, and was also found to involve in murine limb development. Expression of the miR-29 family was found to
suppress by SOX9 at least in part through directly binding to the promoter of the primary miR-29a/b1. Also, TGFβ1/3 decreased expression of the miR-29 family whilst Wnt3a did not have any effect. Lipopolysaccharide suppressed the miR-29 family expression in part
through NFκB signalling pathway while the IL-1 strongly induced its expression partly through P38 MAKP signalling. Using luciferase reporter assay, the miR-29 family was showed to suppress the TGFβ, NFκB, and WNT/β-catenin signalling pathways. Gene expression profiles of gain- and-loss-of-function revealed regulation of a large number of previously recognised extracellular matrix-associated genes as well as an additional subset of protease and Wnt signalling pathway-related genes. Among these genes, ADAMTS6, ADAMTS10, ADAMTS14, ADAMTS17, ADAMTS19, FZD3, DVL3, FRAT2, CK2A2 were experimentally validated as direct targets of the miR-29 family.

Linh Le

Papers

The roles of the microrna 29 family in cartilage homeostasis and osteoarthritis