Role of MicroRNA in Osteoarthritis
Mingcai Zhang1, Kate Lygrissea1 and Jinxi Wanga1,2*
1Harrington Laboratory for Molecular Orthopedics, Department of Orthopedic Surgery, University of Kansas Medical Center, Kansas City, Kansas, USA
2Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
- Corresponding Author:
- Jinxi Wang
Department of Orthopedic Surgery
University of Kansas Medical Center
3901 Rainbow Boulevard, MS #3017
Kansas City, KS 66160, USA
Received Date: April 11, 2017; Accepted Date: April 24, 2017; Published Date: April 28, 2017
Citation: Zhang M, Lygrissea K, Wanga J (2017) Role of MicroRNA in Osteoarthritis. J Arthritis 6:239. doi:10.4172/2167-7921.1000239
Copyright: © 2017 Zhang M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Although the potential effect of aberrant expression of catabolic and anabolic genes on the development of osteoarthritis (OA) is well-documented, the regulatory mechanism for the expression of these genes in articular chondrocytes remains to be elucidated. The recent advances in epigenetic studies have identified microRNA (miRNA) as one of the epigenetic mechanisms for the regulation of gene expression. This mini review highlights the role of miRNA in the regulation of gene expression in articular chondrocytes and its significance in the pathogenesis of OA, with a discussion on the potential of miRNA as a new biomarker and therapeutic target for OA. Further investigations are required to determine the specificity, sensitivity, and efficacy of miRNA for clinical applications
MicroRNA; Osteoarthritis; Epigenetics; Gene expression;
OA: Osteoarthritis; MiRNA: MicroRNA; NcRNA:
Non-coding RNA; MRNA: Messager; RNA; SiRNA: Short Interfering
RNA; piRNA: Piwi-interacting RNA; ECM: Extracellular matrix;
ADAMTS: A Disintegrin and Metalloproteinase with
Thrombospondin Motifs; MMP13: Matrix Metalloproteinase 13;
COL2: Type II Collagen; IL-1β: Interlukin 1-β; COL9: Type IX
Collagen; TNF-α: Tumor Necrosis Factor-α; Runx2: Runt-Related
Transcription Factor 2; NFAT: Nuclear Factor of Activated T-cells.
In contrast to genetics which is the study of hereditable variation in
DNA sequences, epigenetics refers to the study of the changes in gene
transcription activity caused by mechanisms other than changes in
DNA sequences. Traditional epigenetic covalent modifications include
DNA methylation and histone protein modifications (e.g. acetylation,
methylation, phosphorylation, ubiquitination and sumoylation).
Recently, non-coding RNAs (ncRNAs) that possess epigenetic-like
properties in the regulation of gene expression have also been
considered as one of the epigenetic mechanisms [1,2]. With the use of
high-throughput technologies, comprehensive assessment of the
quantity of transcriptional molecules, including protein-coding
messenger RNAs (mRNA) and ncRNAs, is now an area of rapid
expansion in biomedical research of common diseases, such as
OA is the most common form of arthritis and is the leading cause of
chronic disability in middle-aged and older populations . Aberrant
gene expression in articular chondrocytes of OA joints has been well
documented in both animal and humans studies. However, the
underlying regulatory mechanism that causes aberrant gene expression
in OA cartilage has not yet been elucidated.
This review will first highlight the role of microRNA (miRNA), one
of the most studied ncRNAs, in the regulation of aberrant gene expression in articular chondrocytes as it relates to the pathogenesis of
OA, and then discuss the potential use of miRNA as a biomarker and
potential therapeutic target for OA.
miRNA and OA
Biogenesis of miRNA
Classically, a gene is assumed to be transcribed into an mRNA and
then translated into a protein; however, the discovery of genes
encoding ncRNAs has extended the definition of a gene. The ncRNA
genes produce transcripts functioning as structural, catalytic, or
regulatory RNAs rather than being translated into proteins. Based on
their length, ncRNAs can be divided into short ncRNAs (<30
nucleotides) and long ncRNAs (lncRNAs, >200 nucleotides). Short
ncRNAs include miRNAs, short interfering RNAs (siRNAs), and piwiinteracting
RNAs (piRNAs) . MiRNAs are transcribed from miRNA
genes as long primary transcripts (pri-miRNAs) characterized by a
hairpin structure and are processed as pre-miRNAs (around 70-
nucleotides long) in the nucleus. After being transported into the
cytoplasm, pre-miRNAs are cleaved by Dicer and then matured into
miRNA of 22-24 nucleotides .
Aberrant gene expression in OA cartilage
Adult articular cartilage is an avascular tissue in which
chondrocytes are the only cellular component. Articular chondrocytes
maintain the low-turnover of the extracellular matrix (ECM) by
delicately regulating the expression of catabolic and anabolic genes.
Progressive degradation of articular cartilage ECM is the major
pathophysiological feature of OA. Increased expression of catabolic
genes and decreased expression of anabolic genes are usually observed
in OA chondrocytes, which disrupt the metabolic balance in articular
A number of catabolic genes have been proposed to be involved in
the development of OA, including the genes encode: 1) Aggrecanases,
such as ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-4 and -5, two major aggrecanases which have
been shown to play important role in development of OA [6-9]; 2)
Collagenases, particularly MMP (matrix metalloproteinase)-13, a
major type II collagen (COL2A1)-degrading collagenase, which
contributes to the initiation and progression of OA [10,11]; 3) Proinflammatory
cytokines, such as IL (interleukin)-1β, IL-6, and TNF-α
(tumor necrosis factor)[12,13]; 4) RunX2 (Runt- related transcription factor 2), which contributes to the pathogenesis of OA by promoting
chondrocyte hypertrophy and matrix breakdown in articular cartilage.
Runx2+/- mice exhibit decreased cartilage destruction and osteophyte
formation, along with reduced expression of type X collagen and
MMP-13, as compared with wild-type mice . Upregulation of these
catabolic genes contributes to the increased degradation of articular
A number of anabolic genes have been proposed to be involved in
the structure and function of articular cartilage, including the genes
encode: 1) Aggrecan, a major proteoglycan in articular cartilage
[15,16]; decreased aggrecan expression is often evident in OA cartilage
[17,18]. 2) Collagens, collagen type II is one of the major ECM
components of the articular cartilage. Mice bearing a small deletion
mutation in type II collagen gene developed OA-like lesions . 3)
SOX9 (SRY-Box 9), SOX9 is a master transcription factor for
chondrogenesis during the development of the skeletal system, in
cooperation with SOX5 and SOX6 [20,21]. Although mice with
conditional postnatal deletion of Sox9 in chondroytes do not develop
OA , later OA usually is associated with decreased SOX9
expression . 4) NFAT1 (Nuclear Factor of Activated T-cells 1),
which is a member of the NFAT transcription factor family originally
identified as a regulator of the expression of cytokine genes during the
immune response [24,25]. NFAT1 has recently been shown to play an
important role in maintaining the permanent cartilage phenotype in
adult mice. Nfat1 knockout (Nfat1-/-) mice exhibit normal skeletal
development, but display over-expression of numerous matrixdegrading
proteinases and pro-inflammatory cytokines, as well as loss
of collagen-2 and aggrecan during the early stage of OA. These initial
changes are followed by articular chondrocyte clustering, formation of
chondro-osteophytes, progressive articular surface destruction,
formation of subchondral bone cysts, and exposure of thickened
subchondral bone, all of which resemble human OA . Down
regulation of these anabolic genes contributes to the decreased ECM
synthesis, impairing the repair ability of articular cartilage.
Regulation of gene expression in OA by miRNAs
The importance of epigenetic regulation of gene expression to the
development of OA has recently been reported [27-29]. A number of miRNAs have been identified to be involved in the pathogenesis of OA
in recent epigenetic studies. miRNAs may directly bind to catabolic
and anabolic mRNAs to regulate their expression at a posttranscriptional
level in cytoplasm with a complimentary sequence to
induce cleavage and degradation, or block translation [30-32]. New
findings indicate that the regulatory effect of miRNAs on the
expression of catabolic and anabolic genes in OA may take place at
upstream levels prior to their transcription. First, miRNAs target
upstream signaling pathways or transcription factors. The activity of
several signaling pathways, such as NF-kappaB pathway [33,34], Wnt/
beta-Catenin pathway , SIRT1/p53 pathway  and SDF1/
CXCR4 pathway , were found to be modulated by miRNAs in
chondrocytes during the development of OA. Moreover, miRNAs have
also been reported to regulate transcription factor SOX9 in the
development of OA [38,39]. Second, miRNAs target upstream
epigenetic factors. Histone deacetylase-2 , -4 [41-43], and NADdependent
deacetylase sirtuin-1  have been found to be regulated
by miRNAs in OA cartilage, indicating that the interaction among
different epigenetic mechanisms is involved in OA pathogenesis.
miRNA and treatment of OA
The development of disease-modifying pharmacologic therapy for
OA currently faces major obstacles largely because the pathogenesis of
OA remains unclear. The aberrant expression catabolic and anabolic
genes is a well-characterized molecular finding in OA; however,
clinical trials targeting a single inflammatory mediator or proteinase
did not slow the progression of OA [45-47]. This is probably due to the
involvement of multiple factors in the pathogenesis of OA. In this
regard, upstream molecular regulators would be more favorable
MiRNAs could be potential upstream targets for treatment of OA as
one miRNA may regulate several genes. Furthermore, miRNAs
regulate gene expression in OA cartilage at multiple levels and in a
sequence-specific manner [48,49]. However, a large number of
miRNAs have recently been identified in OA joint tissues, and one
gene may be regulated by several miRNAs (Table 1). Further
investigations are needed to identify the articular cartilage specific
miRNA(s) and to validate their efficacy in animal models of OA and in
patients with OA. Specific transcription factors that regulate multiple
catabolic and anabolic genes, such as NFAT1 [26,27,29], could also be
potential upstream targets for treatment of OA.
||Change in OA
HSA: Homo Sapiens; H: Human; M: Mouse; R: Rat↑: Upregulation; ↓: Down Regulation
Table 1: Summary of differentially expressed miRNAs and their target(s) in OA cartilage
miRNA and OA biomarker
Currently, X-ray and MRI (magnetic resonance imaging) are the
established methods for the diagnosis of OA in clinical practice [30-49]. However, specific blood testing that can be used to aid in the
diagnosis and monitoring of OA progression is still under
development. Clinicians and scientists are striving for a novel
molecule(s) which can be used as a biomarker for early OA detection and for monitoring the progression of OA . Given the high
frequency of miRNAs expression in OA and the remarkably stable
form of miRNAs present in clinical samples of plasma and serum
[51,52], miRNAs could be ideal blood-based biomarkers for OA .
However, more studies are needed to identify the OA-specific miRNAs
with high sensitivity to OA changes.
The recent advances in epigenetic studies have shed light on the
importance of miRNAs in regulation of gene expression at multiple
levels related to the pathogenesis of OA [54-65]. This warrants the
potential of miRNAs as therapeutic targets for OA. The tissuespecificity
and high frequency of miRNA expression in OA renders
miRNAs novel molecules as potential biomarkers for diagnosing OA,
monitoring OA progression, and evaluating treatment efficacy. Further
studies are required to identify which miRNAs out of the large number
of miRNAs reported in the literature (Table 1) have high specificity,
sensitivity and efficacy and could be used for clinical validation in OA
This work was supported by the U.S. National Institute of Health
(NIH) under the Award Number R01 AR059088 (to J. Wang).
Conflicts of Interest
The authors declare no conflicts of interest
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