Intertwined roles of microRNA-155 and metformin in osteoarthritis: Novel potential diagnostic, prognostic, and therapeutic modulators

Figure 6 Schematic known and potential metformin actions on chondroprotection, immunomodulation, circadian rhythmicity, and pain reduction resulting in improved osteoarthritis management. Metformin reduces the catabolism and apoptosis of chondrocytes, regularizes the circadian disruptions observed in osteoarthritis (OA), and decreases the infiltration and M1 polarization of synovial macrophages. Metformin is able to modulate microRNA-155 expression but whether this ability mediates its effects systemically and in OA is currently unknown. Light orange and purple boxes indicate molecular metformin effects while light green boxes indicate metformin tissue effects. Detailed gene functions and gene abbreviations can be found in Table 2. AMPK: Adenosine monophosphate-activated protein kinase; Bmal1: Brain and muscle Arnt-like protein 1; CLOCK: Circadian locomotor output cycles kaput; Cas-1: Caspase-1; COX-2: Cyclooxygenase 2; ECM: Extracellular matrix; ERK: Extracellular regulated protein kinases; GI: Gastrointestinal; GSDMD: Gasdermin D; HIF-1α: Hypoxia-inducible factor 1 alpha; IL: Interleukin; MiR-155: MicroRNA-155; MMP: Metalloproteinase; mTORC1: Mammalian target of rapamycin C1; MΦ: M1 macrophage; NF-κB: Nuclear factor kappa-B; NLRP3: NOD-like receptor family pyrin domain-containing 3; Nrf2: Nuclear factor erythroid-2-related factor 2; PER: Period; PTEN: Phosphatase and tensin homolog; ROS: Reactive oxygen species; Runx2: Runt-related transcription factor 2; SIRT1: Sirtuin 1; Sox9: SRY-related HMG box 9; TNF-α: Tumour necrosis factor-alpha; ↓: Decline; ↑: Increase.