Table 1.
Roles of metformin in OA.
| Intervention | Experimental Model | Mechanism of Action | Consequences | References |
|---|---|---|---|---|
| Metformin 200 mg/kg, oral, once daily for 8 weeks; metformin 0.1 mmol/kg, i.e., injection, twice a week for 8 weeks | DMM-induced mouse OA model | Decrease the level of MMP-13, but elevate Col II production by activating the AMPK pathway. | Attenuate OA structural deterioration and relieve pain. | [17] |
| Metformin dissolved in DMSO for in vitro assay | IL-1β-induced murine OA chondrocytes | Upregulate the expression of SIRT3; mitigate the loss of cell viability; and decrease the generation of mitochondria-induced ROS. | Suppress oxidative and OA-like inflammatory changes by enhancing the SIRT3/PINK1/Parkin signaling pathway. | [33] |
| Metformin 4 mg/d, oral, 2 weeks | DMM-induced mouse OA model; partial medial meniscectomy animal model of nonhuman primates | Upregulate the expressions of phosphorylated and total aMPK. | Inhibit cartilage degradation, synovial hyperplasia and osteophyte formation. Limit OA development and progression through AMPK signaling. | [38] |
| Metformin 10 mg/kg + alendronate 20 mg/kg, i.a. injection, 10 times (every other day from day 0 to day 18) | Collagenase-induced mouse OA model | Inhibit the expressions of RANK and RANKL on osteoblasts and osteoclasts; suppress the differentiation of both MSCs and fibroblasts; decrease the serum concentrations of leptin and resistin in the chronic phase of arthritis. | Decrease the degree of cartilage degeneration. | [39] |
| Metformin 100 mg/kg/d or 200 mg/kg/d, oral | DMM-induced mouse OA model | Decrease the p16INK4a level in OA chondrocytes; enhance the polarization of AMPK; and inhibit mTORC1 in OA mice and chondrocytes. | Alleviate cartilage degradation and aging by regulating the AMPK/mTOR signaling pathways. | [40] |
| Metformin 1 mM for 24 h | IL-1β-induced murine OA chondrocytes | Increase the proliferation of chondrocytes; alleviate the IL-1β-induced ECM metabolic imbalance and proinflammatory cytokine production; exert the anti-apoptosis activity. | Protect chondrocytes by regulating the AMPK/NF-κB signaling pathway. | [41] |
| Metformin 1.65 g/mL, i.a. injection, once every 3 days for 8 weeks | DMM-induced mouse OA model | Restore the upregulation of MMP-13 and downregulation of Col II; increase the phosphorylated level of AMPKa and upregulate the expression of SIRT1 protein. | Increase autophagy and decrease catabolism and apoptosis by activating the AMPKa/SIRT1 signaling pathways. | [42] |
| Metformin 200 mg/kg/d, oral, 4 or 8 weeks | DMM-induced mouse OA model | Increase the expression of Col II and decrease the expressions of MMP-13, NLRP3, caspase-1, GSDMD and IL-1β. | Decrease the OARSI score, increase the thickness of hyaline cartilage, and decrease the thickness of calcified cartilage. | [43] |
| Metformin 100 mg/kg/d + celecoxib 80 mg/kg/d, oral, 14 days | MIA-induced rat OA model; chondrocytes from OA patients | Reduce the catabolic factor gene expression and the expression of inflammatory cell death factor; increase the expressions of LC3IIb, p62, and LAMP1; and induce an autophagy–lysosome fusion phenotype. | Suppress pain and protect cartilage. | [44] |
| Metformin-stimulated MSCs, i.v. injection | MIA-induced rat OA model | Increase the expressions of IL-10 and IDO in Ad-hMSCs and decrease the expressions of high-mobility group box 1 protein, IL-1β, and IL-6; improve the migration capacity of Ad-hMSCs by upregulating the expression of chemokine. | Exert the anti-nociceptive activity and chondroprotective effect. | [45] |
| Metformin 100 mg/kg/d + exercise 30 min/d, oral, 8 weeks | Estrogen deficiency and obesity induced mouse OA model | Increase the expressions of aggrecan and type II collagen (Col II) and decrease the expression of ADAMTS-4; increase the concentration of osteocalcin and decrease the serum concentrations of IL-1β, CTX-1 and glucose. | Ameliorate the abnormal metabolic status and cartilage lesions. | [46] |
| Metformin + COX-2 inhibitor, oral | Patients with OA and T2D | Lower the rate of receiving joint replacement surgery. | Result in a lower joint replacement surgery rate. | [47] |
| Metformin, oral | Obese patients with knee OA | Decrease the medial cartilage volume loss; associate with a trend towards a significant reduction of the risk of TKA. | Generate a beneficial effect on the long-term knee joint outcome. | [48] |
| Metformin 100 mg/kg/d, oral, 4 or 8 weeks | DMM-induced mouse OA model | Suppress the RANKL-induced activation of p-AMPK, NF-κB and pERK and the up-regulation of genes involved in osteoclastogenesis; reverse the decreases in BV/TV, Tb.Th, Tb.N, and connectivity density and the increase in Tb.Sp. | Inhibit the osteoclast formation and bone resorption in a dose-dependent manner in early OA. | [49] |
Note: Ad-hMSCs, adipose tissue-derived human mesenchymal stem cells; ALT, alanine aminotransferase; AMPK, adenosine monophosphate-activated protein kinase; CTX-1, C-telopeptide of type I collagen; Col II, collagen type II; DMM, destabilization of the medial meniscus; DMSO, dimethyl sulfoxide; ECM, extracellular matrix; GSDMD, gasdermin D; IL-1β, interleukin-1β; MIA, monosodium iodoacetate; MMP-13, matrix metalloproteinase-13; mTORC1, mammalian target of rapamycin complex 1; MSCs, mesenchymal stem cells; NF-κB, nuclear factor kappa-B; NLRP3, NOD-like receptor protein 3; i.a., intra-articular; OARSI, Osteoarthritis Research Society International; pERK, phosphorylated extracellular regulated protein kinases; RAGE, receptor for advanced glycation end products. RANKL, receptor activator of nuclear factor kappa-B ligand; ROS, reactive oxygen species; SIRT, silent mating type information regulation 2 homolog; T2D, type 2 diabetes; TKA, total knee arthroplasty; IL-6, interleukin-6; CRP, C-reactive protein; TNF-α, tumor necrosis factor alpha; NASH, Nonalcoholic steatohepatitis; TGF-β, transforming growth factor-β.