Metformin improves monosodium-iodoacetate-induced osteoarthritis via regulation of pain mediators and autophagy-lysosomal pathway

Background Osteoarthritis (OA) is the most common degenerative arthritis associated with pain and cartilage destruction in the elderly. Its pathogenesis involves inflammatory pathways. Metformin is used to treat type 2 diabetes but also exhibits regulation of autophagy pathway. This study investigated the ability of metformin to ameliorate the severity of monosodium iodoacetate (MIA)-induced OA in rats. Methods Metformin was administered orally every day to rats with OA experimentally induced by intra-articular injection of MIA. Paw-withdrawal latency and threshold were used to assess pain severity. Cartilage damage and pain mediators in dorsal root ganglia were evaluated by histological analysis and a scoring system. Relative mRNA expression was measured by real-time PCR. Results Metformin ameliorated the progression of experimental OA and exhibited both anti-nociceptive properties and cartilage protection. The metformin-induced down-regulation of pain mediators, including CGRP, in dorsal root ganglia and protection against bone damage were also determined. In chondrocytes from OA patients, metformin decreased expression of genes encoding catabolic factors stimulated by interleukin-1β and inflammatory cell death factors and induced autophagosome–lysosome fusion phenotype. The combination therapy of metformin and celecoxib had significantly less cartilage damage than either the metformin alone group or the control group. Conclusions These results imply the possibility of therapeutic use of metformin in OA patients, based on its ability to suppress pain and protect cartilage.