MicroRNAs or miRNAs are members of transcribed DNA fragments that do not proceed

to translation to serve as templates for peptide synthesis. Such RNAs are collectively called as
non-coding RNAs (ncRNAs) which also include transfer RNAs (tRNAs), ribosomal RNA
(rRNAs), short interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs), and other longer
types. Although they are not encoding for a protein product, most ncRNAs except tRNAs and
rRNAs, whose main function is in translation, are involved in various regulatory activities. In
human, one third of all protein-coding genes may be regulated by miRNA (Yu, Chen & Wang,
2011).
A 21-25 nucleotide miRNA, the product of a processed pri-miRNA followed by two rounds
of cleavage (by Drosha and Dicer) of the resulting pre-miRNA, regulates a particular
developmental or physiological pathway via gene silencing at post-transcriptional level in a
sequence-specific approach. Depending on the degree of complementarity of the base pairing
between the miRNA and the 3-untranslated region (3-UTR) of the target mRNA, the miRNA
prevents the use of the transcript in protein synthesis either via translational repression or
targeted mRNA cleavage. In translational repression, considered as the more common
mechanism for miRNA-mediated gene silencing, miRNA-3-UTR base pairing is imperfect; such
interaction is theorized to repress translational elongation and not initiation resulting in
repression. Alternatively, when the miRNA-3-UTR base pairing is virtually perfect as in that of
mir-196 and 3-UTR of Hoxb8, the miRNA induces gene silencing via cleavage of the target
transcript (He & Hannon, 2004).
With their roles in lipid metabolism, apoptosis, differentiation and organ development,
miRNAs have been noted as one of the epigenetic modifications influential to the development
of osteoarthritis. Their regulatory activity on genes for the synthesis (anabolic) and breakdown
(catabolic) of the extracellular matrix (ECM) of articular cartilage have been established to effect
the pathogenesis of OA. In essence, OA is characterized by elevated miRNAs that repress the
expression of anabolic genes and stimulate the expression of catabolic genes, and reduced
miRNAs that increase the expression of anabolic genes and decrease the expression of
catabolic genes resulting in net loss of articular cartilage ECM. Recent studies, however,
suggest that these interactions between miRNAs and ECM genes are indirect and are mediated
by upstream signaling pathways or transcription factors. Thus, miRNA regulation of anabolic
and catabolic genes occurs before transcription. Moreover, miRNA could also regulate other
epigenetic factors related to OA such as histone deacetylases (HDACs) demonstrating the
interaction among different epigenetic mechanisms in the development of OA (Zhang, Lygrisse
& Wang, 2017).
1. Mir140
Compared with normal cartilage, miR140 expression is considerably lower in OA cartilage. As
such, the miRNAs target elements that it stimulates are also downregulated such as histone
deacetylase 4 (HDAC4), and those that it represses are upregulated such as Smad3 and
interleukin-1 (IL-1) which then induce the development of OA. In cartilage tissues of mouse
embryos, Tuddenham et al. (2006) established the repression of HDAC4 by miR140. Decreased
miR140 inhibits the antagonistic activity of the enzyme to OA-related genes which include
catabolic genes (MMPs, ADAMTS), IL-1, Cox2, iNos, Ihh and type X collagen leading to their
overexpression characteristic of OA at the molecular level (Cao et al., 2014). Similarly, direct
and indirect stimulation of IL-1 by the under-expressed miR140 in OA cartilage enforce
ADAMTS5 upregulation and aggrecan, an anabolic gene, downregulation (Miyaki et al., 2009).
On the other hand, Pais et al. (2010) showed that miR140 suppresses SMAD 3 which is
involved in TGF pathway. Such signaling directs OA pathogenesis by driving chondrocytes
toward hypertrophy, promoting osteoprogenitor cell differentiation into osteoblasts and
angiogenesis in subchondral bone, and stimulating synovial lining cells expansion and fibrosis
(Shen, Li & Chen, 2014). In OA, the miR140-mediated repression of the pathway is reduced.

2. Mir22

Elevated miR22 expression has been found to suppress PPARA and BMP7 expression at the
mRNA and protein level, respectively. Consequently, the activity of the two target genes that
contributes to aggrecan production is also inhibited leading to osteoarthritis. At the same time,
the expression of IL- and MPP-B which are associated to OA pathogenesis is stimulated
(Goldring & Marcu, 2012)
3. Mir27a

Some miRNA, though not directly affecting genes involved in the development of OA, may
increase the risk for the disease when dysregulated. For instance, miR27a, by inhibiting
peroxisome activated receptor- at post-transcription, causes decreased adipocyte
differentiation. As a transcription factor, PPAR binds to the promoters of adipocyte specific
genes allowing it to direct adipocyte differentiation (Motawi et al., 2017). In OA, the decrease in
expression of the miRNA results in dysregulation of adipocyte differentiation (i.e. increased
adipocyte differentiation). This then leads to obesity which is a strong risk factor for OA (Yu,
Chen & Wang, 2011).

References:
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Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration
by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing
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