Abstract
Osteoarthritis (OA) is the most common degenerative joint disease. One of the main pathogenic factors of OA is thought to be inflammation. Other factors associated with OA are dysregulation of microRNAs, reduced autophagic activity, oxidative stress, and altered metabolism. microRNAs are small non-coding RNAs that are powerful regulators of gene expression. miR-140-5p is considered a cartilage-specific microRNA, is necessary for in vitro chondrogenesis, has anti-inflammatory properties, and is downregulated in osteoarthritic cartilage. Its passenger strand, miR-140-3p, is the most highly expressed microRNA in healthy cartilage and increases during in vitro chondrogenesis. miR-146a is a well-known anti-inflammatory microRNA. Several studies have illustrated its role in OA and autoimmune diseases. We show that, when human chondrocytes were transfected individually with miR-140-5p, miR-140-3p, or miR-146a prior to stimulation with interleukin-1 beta and tumor factor necrosis-alpha as an inflammatory model of OA, each of these microRNAs exhibited similar protective effects. Mass spectrometry analysis provided an insight to the altered proteome. All three microRNAs downregulated important inflammatory mediators. In addition, they affected different proteins belonging to the same biological processes, suggesting an overall inhibition of inflammation and oxidative stress, enhancement of autophagy, and restoration of other homeostatic cellular mechanisms, including metabolism.
Highlights
Osteoarthritis (OA) is the most common degenerative joint disease, affecting 10%–13% of adults in western countries.[1,2] There is yet no disease modifying treatment available
Increased levels of the inflammatory cytokines interleukin 1 beta (IL-1b) and tumor necrosis factor alpha (TNF-a) in the joint fluid have been associated with the development of OA.[4,6,7]
The miRNAs were detected at much higher levels compared with cells transfected with a negative control sequence (Figure 2A)
Summary
Osteoarthritis (OA) is the most common degenerative joint disease, affecting 10%–13% of adults in western countries.[1,2] There is yet no disease modifying treatment available. The exact causes of OA are unknown, but several risk factors have been identified, such as age, trauma, obesity, genetics, and other joint pathologies.[3] Inflammation is considered a major factor associated with the risk of cartilage loss and OA perpetuation.[4,5] At the molecular level, cartilage destruction occurs through the combined activities of cartilage degradation enzymes and inflammatory mediators. Increased levels of the inflammatory cytokines interleukin 1 beta (IL-1b) and tumor necrosis factor alpha (TNF-a) in the joint fluid have been associated with the development of OA.[4,6,7] Autophagy is an essential mechanism that ensures cellular homeostasis by degrading and recycling cellular components. Autophagy regulates expression of inflammatory cytokines, is compromised in aging cartilage,[8,9] is defective in human OA chondrocytes and animal OA models, and can be regulated by microRNAs (miRNAs).[10,11,12,13]
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