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

Figure 3 Schematic representation of microRNA-155 circadian clock effects and mitochondrial dynamics disruption. The 24-hour circadian locomotor output cycles kaput, brain and muscle Arnt-like protein 1 (Bmal1), period, and cryptochrome (CRY) feedback loop forms a cellular clock in cartilage. Loss of Bmal1 in osteoarthritic (OA) chondrocytes diminishes SRY-related HMG box 9, Aggrecan-(ACAN), and type II collagen (Col2a1), driving cartilage catabolism and degeneration. Elevated microRNA-155 (miR-155) in OA can directly repress Bmal1 and hypoxia-inducible factor 1 alpha, activating nuclear factor kappa-B-mediated inflammation and extracellular matrix (ECM) breakdown. Elevated miR-155 in OA increases the expression of mitofusin 2 and induce cellular senescence by promoting mitochondrial fusion. MiR-155 induced calcium-binding protein 39/p-adenosine monophosphate-activated protein kinase downregulations further aggravate senescence. CCAAT/enhancer-binding protein beta repression and downregulation of its downstream target genes nuclear factor erythroid 2-related factor 2, superoxide dismutase 1, and hemeoxygenase-1 induce reactive oxygen species (ROS) generation and disrupt ROS scavenging, perpetuating mitochondrial dysfunction. MiR-155 also impairs mitochondrial oxidative phosphorylation by repressing Arginase 2 (ARG2) and inhibiting ARG2-mediated increases of mitochondrial complex II activity at the electron transport chain. Gene functions and gene abbreviations can be found in Table 2. AMPK: Adenosine monophosphate-activated protein kinase; ARG2: Arginase2; Bmal1: Brain and muscle Arnt-like protein 1; CLOCK: Circadian locomotor output cycles kaput; CRY: Cryptochrome; C/EBPβ: CCAAT/enhancer-binding protein beta; ECM: Extracellular matrix; HIF-1α: Hypoxia-inducible factor 1 alpha; HMOX1: Hemeoxygenase-1; Mfn2: Mitofusin 2; MiR-155: MicroRNA-155; MMP: Metalloproteinase; NFE2 L2: Nuclear factor, erythroid 2 like 2; NLRP3: NOD-like receptor family pyrin domain-containing 3; OA: Osteoarthritic; OXPHOS: Oxidative phosphorylation; PER: Period; ROS: Reactive oxygen species; Runx2: Runt-related transcription factor 2; SOD1: Superoxide dismutase 1; Sox9: SRY-related HMG box 9; ↓: Decline; ↑: Increase.