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

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, synovial inflammation, and subchondral bone remodelling. Despite its increasing prevalence, effective diagnostic, disease-limiting, and therapeutic strategies remain unattainable. Recent studies have recognized the involvement of microRNA-155 (miR-155) in the pathogenesis of OA and most of its risk factors while also identifying the antidiabetic drug metformin as a potential modulator of disease progression. MiR-155, a key endogenous regulator of the immune system, mechano-transduction, and multiple genetic pathways, interacts with OA targets of cellular energetic and circadian homeostasis, promoting systemic and local articular inflammation, cartilage matrix degradation, and chondrocyte apoptosis. Metformin, widely used for type 2 diabetes, has demonstrated anti-inflammatory, anti-oxidative, and chondroprotective properties in OA, mainly through its activation of adenosine monophosphate-activated protein kinase and inhibition of nuclear factor kappa-B signalling. Enthrallingly, metformin targets the same cellular pathways as miR-155 with emerging evidence also suggesting miR-155 expression modulation, indicating synergistic, potentially disease-modifying effects in OA. This review highlights the central role of miR-155 in OA pathophysiology and its potential as a biomarker for disease diagnosis and progression. MiR-155 targeting - through microRNA therapeutics (mimics/antagomiRs) and/or metformin - could pave the way for innovative treatments, including novel articular delivery systems and cell-based therapies.