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

Figure 5 Schematic depiction of known microRNA-155 targets in osteoarthritis and associations with the four main osteoarthritis pathologies: Inflammation, extracellular matrix degradation, chondrocyte senescence and subchondral bone remodeling. MicroRNA-155 (miR-155) is a fundamental mediator of obesity outcomes and abnormal mechanical overload articular effects through aggravated inflammation, accelerated chondrocyte senescence and autophagy interference, while at the same time it disrupts circadian and metabolic chondrocyte homeostasis promoting further catabolism and inflammation through brain and muscle Arnt-like protein 1 (Bmal1)/adenosine monophosphate-activated protein kinase (AMPK) and Bmal1/hypoxia-inducible factor 1 alpha (HIF-1α) interactions. Finally, disrupted mitochondrial function with impaired oxidative phosphorylation and enhanced glycolysis is engendered through miR-155-induced alterations in AMPK/calcium-binding protein 39, Arginase 2, and CCAAT/enhancer-binding protein beta/nuclear factor erythroid 2-related factor 2, hemeoxygenase-1/superoxide dismutase 1 downstream signalling affecting mitochondrial dynamics, reactive oxygen species clearance and promoting key glycolytic enzymes. Moreover, miR-155 influences AMPK/sirtuin 1/HIF signalling balancing chondrocyte energy generation in hypoxia. Metformin can modulate Prkaa1, cyclooxygenase 2 and miR-155. The colours of the 4 main OA pathologies are the same as on the genes that influence them. Arrows indicate interactive effects. Detailed gene functions and gene abbreviations can be found in Table 2. AGTR1: Angiotensin II type 1 receptor gene; ARG2: Arginase2; BACH1: BTB and CNC homology 1, basic leucine zipper transcription factor 1; Bmal1: Brain and muscle Arnt-like protein 1; CASP3: Caspase 3; COX-2: Cyclooxygenase 2; C/EBPβ: CCAAT/enhancer-binding protein beta; ECM: Extracellular matrix; Ets-1: E26 transformation-specific sequence-1; GDF6: Growth differentiation factor 6; HIF-1α: Hypoxia-inducible factor 1 alpha; IGF-1: Insulin-like growth factor 1; IKBKE: Inhibitor of nuclear factor kappa-B kinase subunit epsilon; LEPR: Leptin receptor; Mafb: Musculoaponeurotic fibrosarcoma oncogene family, protein B; MAPK: Mitogen-activated protein kinase; Mfn: Mitofusin; MiR-155: MicroRNA-155; NF-κB: Nuclear factor kappa-B; RANKL: Receptor activator of nuclear factor kappa-B ligand; Runx2: Runt-related transcription factor 2; SHIP-1: Src homology 2-containing inositol phosphatase-1; SIRT1: Sirtuin 1; Smad: Mothers against decapentaplegic homolog 4; SOCS1: Suppressor of cytokine signaling 1; SOD: Superoxide dismutase; TNF-α: Tumour necrosis factor-alpha.