ArticleClinical rheumatology2026
Dose-dependent histopathological and immunohistochemical effects of metformin in experimental osteoarthritis.
Article in Clinical rheumatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveTo evaluate the dose-dependent effects of metformin on joint pathology and inflammatory and apoptotic processes in a monosodium iodoacetate (MIA)-induced rat model of osteoarthritis.
methodsForty male Wistar albino rats were randomized into four groups (n = 10): sham control, OA, MIA + metformin 100 mg/kg, and MIA + metformin 200 mg/kg. OA was induced by intra-articular injection of 3.5 mg MIA. Metformin was administered intraperitoneally for 30 days. Spontaneous pain-related behavior was scored with a semi-quantitative, non-reflexive system. Histopathological parameters and IL-1β, IL-6, TNF-α, caspase-3, and LC3 expression were examined.
resultsCompared with control, the OA group worsened across all histopathological parameters (p < 0.01). Immunohistochemically, IL-1β, IL-6, TNF-α, and caspase-3 expression increased, whereas LC3 expression decreased (p < 0.01). Histopathological severity and marker profiles changed in an ordered manner across the untreated OA and both metformin groups (Jonckheere-Terpstra, two-sided p < 0.001). After adjustment for six pairwise comparisons, the 200 mg/kg group differed from untreated OA on every tissue parameter, whereas the 100 mg/kg group did not reach the adjusted threshold for histopathology despite large effect sizes (Cliff's delta 0.85 to 1.00). Pain-related behavior improved from day 3 to day 30 in both metformin groups (100 mg/kg: p = 0.005; 200 mg/kg: p = 0.028), whereas at day 30 only the 200 mg/kg group differed from untreated OA (adjusted p = 0.002).
conclusionsMetformin showed chondroprotective and anti-inflammatory effects with reduced apoptotic marker expression and altered autophagy-related signaling, attenuating cartilage degeneration in a dose-dependent manner. Improvement in pain-related behavior compared with untreated OA was significant only at 200 mg/kg. Key Points • Metformin started on the day of MIA induction attenuated structural joint damage at day 30. • Histopathological and immunohistochemical outcomes showed an ordered dose-related pattern across untreated OA, 100 mg/kg, and 200 mg/kg groups. • Treatment was accompanied by reduced inflammatory and apoptotic marker expression and altered autophagy-related signaling. • At day 30, improvement in pain-related behavior was significant compared with untreated OA only at 200 mg/kg.
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