Dose-dependent histopathological and immunohistochemical effects of metformin in experimental osteoarthritis
Abstract
Objective: To 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.
Methods: Forty 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.
Results: Compared 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…
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