The Role of miRNAs in Common Inflammatory Arthropathies: Osteoarthritis and Gouty Arthritis

Abstract

MicroRNAs (miRNAs) are small, non-coding RNA species that are highly evolutionarily conserved, from higher invertebrates to man. Up to 1000 miRNAs have been identified in human cells thus far, where they are key regulators of the expression of numerous targets at the post-transcriptional level. They are implicated in various processes, including cell differentiation, metabolism, and inflammation. An expanding list of miRNAs is known to be involved in the pathogenesis of common, non-autoimmune inflammatory diseases. Interestingly, osteoarthritis (OA) is now being conceptualized as a metabolic disease, as there is a correlation among hyperuricemia and metabolic syndrome (MetS). Experimental evidence suggests that metabolic deregulation is a commonality between these different pathological entities, and that miRNAs are key players in the modulation of metabolic routes. In light of these findings, this review discusses the role of miRNAs in OA and gouty arthritis, as well as the possible therapeutic targetability of miRNAs in these diseases.

Keywords: arthropathy; cartilage erosion; hyperuricemia; metaflammation; monosodium urate crystals; overweight; post-transcriptional regulator.

Figure 1

Intronic microRNAs (miRNAs) and the miRNA-488/ZIP8/MTF1 pathway are critically involved in the pathogenesis of osteoarthritis (OA). Distinct miRNAs (miRNA-33a, miRNA-455-3p, miRNA-140, and miRNA-335-5p) reside within intronic regions of human genes and they modulate the expression of a series of molecules either positively (upward pointing arrows) or negatively (downward pointing arrows) associated with the development of osteoarthritis. These molecules include proteases responsible for the degradation of cartilage matrix (matrix metalloproteases (MMPs), A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS5)), molecules related with cholesterol synthesis and efflux in OA chondrocytes (sterol regulatory element binding protein 2 (SREBP-2), apolipoprotein A1 (ApoA1), and ATP binding cassette subfamily A member 1 (ABCA1)), or they affect Mothers against decapentaplegic homolog 2/3 (Smad2/3)- and Wingless (Wnt)-dependent signalling. On the other hand, miRNA-488 influences a zinc transporter ZIP8/ metal-regulatory transcription factor 1 (ZIP8/MTF1)-mediated route, which eventually upregulates a set of molecules that are implicated in the enzymatic erosion of articular cartilage, i.e., MMP-3, MMP-13, and ADAMTS5. These molecular events largely contribute to the OA phenotype through promoting pathological changes; erosion of cartilage and meniscus, denudation of the subchondral bone and osteophytosis (see the text for details). Other miRNA-dependent, as well as miRNA-independent, pathways are involved in the pathogenesis of OA. However, they are not depicted here for reasons of simplicity. Intronic miRNAs reside in introns from different loci. A common graph of three exons has been drawn here for reasons of clarity. Key anatomic domains of the knee and their alterations during OA development are indicatively depicted. These molecular events are not only associated with knee osteoarthritis but they may also be localized in other joints.

Figure 2

OA-associated miRNA-dependent pathways may be therapeutically targeted at multiple levels. Dicer-mediated processing of certain pre-miRNAs of the corresponding mature miRNA (guide strand) can be blocked via small molecules that serve as maturation inhibitors (level 1). miRNA mimics can be used to mimic the function of endogenous miRNA molecules (level 2). Oligonucleotides (oligos) complementary to miRNAs, such as antagomiRs and miRNA sponges, can interfere with miRNA:mRNA interactions through hybridization with target miRNAs (level 3). Chemically divergent small molecules, which block the assembly of RNA-induced silencing complex (RISC), designated as RISC loading inhibitors, have been also identified. These inhibitors do not affect argonaute 2 (Ago2) activity or pre-formed miRNA:Ago2 complexes (level 4). On the other hand, miRNA-masking (miRNA MASK) technology (level 5) involves the usage of single-stranded chemically modified oligos, which are complementary to the 3′ untranslated region (UTR) of a target transcript. Therefore, the interaction among miRNA and its target is prevented, and the expression of a gene of interest is derepressed. Overall, the net result of all of the above-mentioned putative therapeutic strategies is the modulation of the expression of different mRNAs that are associated with OA pathogenesis. Note that a miRNA may regulate multiple miRNA targets, while a distinct mRNA may be controlled by more than one miRNA. This phenomenon contributes to the generation of a complicated network of interplaying pathways. ORF: open reading frame; pri-miRNA: primary miRNA.