Imeglimin, a novel antidiabetic agent related to metformin, attenuates knee osteoarthritis development and progression through AMPK activation and NF-κB signaling inhibition.

Abstract

OBJECTIVE: Metformin, a first-line treatment for type 2 diabetes, attenuates hallmarks of aging and protects against age-related diseases, including osteoarthritis (OA). Here, we assessed the effects of imeglimin, a novel antidiabetic agent related to metformin, on the development and progression of knee OA. DESIGN: Primary human OA chondrocytes, synovial cells, and meniscal cells were stimulated with IL-1β and treated with imeglimin (n = 8). OA-related gene and protein expressions were quantified using RT-qPCR and ELISA. Activation of NF-κB and AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, was assessed using western blotting and immunofluorescence. Additionally, we evaluated its efficacy in two knee OA mouse models (n = 10): destabilization of the medial meniscus and medial collateral ligament transection (DMM+MCLT), and monoiodoacetate (MIA)-induced OA pain. RESULTS: Imeglimin suppressed IL-1β-induced expressions of OA-related genes, including pro-inflammatory (IL6, IL1B, TNF), catabolic (MMP13, ADAMTS5), and pain-related (CCL2, NGF) genes, and reduced IL6 secretion. Western blot analysis revealed downregulation of IκBα and p65 activation and AMPK upregulation. Immunocytochemistry confirmed decreased p65 nuclear translocation (-4245 AU; 95% CI -6765 to -1725). Intra-articular administration of imeglimin reduced histological severity of OA in cartilage, synovium, and meniscus in DMM+MCLT mice (OARSI grade, -3.0 [95% CI: -5.0 to -1.0]), decreased the number of cells expressing p-IκBα in the articular cartilage, and attenuated OA pain in both DMM+MCLT and MIA models. CONCLUSIONS: Imeglimin enhances protective functions in joint tissue cells and alleviates experimental OA in preclinical mouse models, supporting its potential as a therapeutic candidate for knee OA.