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

Figure 2 Risk factors in osteoarthritis. Aging, obesity, sarcopenia, type 2 diabetes mellitus (T2DM), and female sex, all important risk factors in osteoarthritis (OA), promote microRNA-155 (miR-155) overexpression in OA through chronic inflammation and mechanical overload that through numerous gene repressions/modulations perpetuate an established global inflammatory state and promote a local articular proinflammatory milieu with elevated metalloproteinase (MMP), disintegrin and MMP with thrombospondin motif (Adamts), Runx2, NOD-like receptor family pyrin domain-containing 3, caspase-1 (Cas-1), Gasdermin D resulting in chondrocyte catabolism and apoptosis, increased chondrocyte senescence, reactive oxygen species generation, autophagy disruption, ultimately contributing to augmented extracellular matrix degradation. Increased miR-155/nuclear factor kappa-B signaling promotes interleukin (IL)-1β/IL-6 secretion, chondrocyte hypertrophy, synovial M1 macrophage recruitment initiating synovial inflammation and subchondral bone remodeling. Adipokines, visfatin and resistin, potentiate miR-155 expression and effects. Piezo-Type Mechanosensitive Ion Channel Component 1 mediates mechanoelectrical transduction of inflammatory responses in the chondrocyte and up-regulates miR-155. Gene functions and gene abbreviations can be found in Table 2. AMPK: Adenosine monophosphate-activated protein kinase; Cas-1: Caspase-1; CASP3: Caspase 3; ECM: Extracellular matrix; GDF6: Growth differentiation factor 6; GSDMD: Gasdermin D; IGF-1: Insulin-like growth factor 1; IKBKE: Inhibitor of nuclear factor kappa-B kinase subunit epsilon; IL: Interleukin; MiR-155: MicroRNA-155; MMP: Metalloproteinase; MΦ: M1 macrophage; NF-κB: Nuclear factor kappa-B; NLRP3: NOD-like receptor family pyrin domain-containing 3; OA: Osteoarthritis; PIEZO1: Piezo-Type Mechanosensitive Ion Channel Component 1; PPARγ: Peroxisome proliferator-activated receptor γ; ROS: Reactive oxygen species; Runx2: Runt-related transcription factor 2; SOCS1: Suppressor of cytokine signaling 1; Sox9: SRY-related HMG box 9; STAT3: Signal transducer and activator of transcription 3; TNF-α: Tumour necrosis factor-alpha; T2DM: Type 2 diabetes mellitus; ↓: Decline; ↑: Increase.