Korean J Intern Med > Volume 37(1); 2022 > Article |
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Study | Results |
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Preclinical | |
Lockwood (2010) [53] | Metformin has anti-lysosomal action and increases anti-lysosomal action of Zn2+. |
Kang et al. (2013) [40] | Metformin attenuated arthritis severity and inhibited Th17 cell differentiation in a CAIA murine model. |
Indo et al. (2013) [51] | Metformin inhibited osteoclast differentiation in vitro. |
Son et al. (2014) [41] | Metformin reduced arthritis severity, suppressed Th17 cell differentiation, enhanced Treg cell differentiation, and suppressed osteoclast differentiation in CIA mice. |
Yan et al. (2015) [54] | Metformin suppressed arthritis severity and inflammatory cytokine production in a K/BxN serum transfer mouse model by enhancing autophagic flux and suppressing the NF-κB pathway. |
Jhun et al. (2016) [55] | Combination of metformin and coenzyme Q10 attenuated arthritis severity, suppressed Th17 cell differentiation, enhanced Treg cell differentiation, suppressed osteoclast differentiation, and recovered mitochondrial function in CIA mice to a greater degree compared to treatment with metformin or coenzyme Q10 alone. |
Kim et al. (2018) [59] | Metformin attenuated arthritis severity, decreased Th17 cell differentiation, increased Treg cell differentiation, and improved metabolic profiles in obese CIA mice by inducing FGF21 expression and brown adipose tissue differentiation. |
Chen et al. (2019) [43] | Metformin inhibited in vitro proliferation of FLS obtained from patients with RA (RA FLS). |
Chen et al. (2020) [44] | Metformin inhibited in vitro proliferation and migration of RA FLS. |
Fan et al. (2020) [47] | Metformin improved synovial inflammation and bone and cartilage destruction in joints of CIA rats. |
Kim et al. (2020) [56] | Combination of metformin and rapamycin attenuated arthritis severity, regulated Th17 and Treg cell balance, and improved metabolic profiles in obese CIA mice compared to rapamycin alone or vehicle treatment. Metformin recovers mitochondrial dysfunction induced by rapamycin. |
Gallagher et al. (2020) [60] | Alteration of glucose metabolism in synovial fibroblasts by metformin resulted in reduced production of inflammatory cytokines in ex vivo RA synovial explant cultures and in vitro RA FLS cultures. |
El-Sayyad et al. (2021) [61] | Combination of metformin and omega-3 attenuated arthritis severity and showed additive anti-inflammatory effects in adjuvant-induced arthritis rats compared to metformin or omega-3 alone. |
Park et al. (2021) [62] | Combination of metformin and LMT-28, an inhibitor of IL-6 signaling, ameliorated arthritis severity by suppressing Th17 cell differentiation, enhancing Treg cell differentiation, and inhibiting IL-6 signaling in CIA mice compared to metformin or LMT-28 alone. |
Matsuoka et al. (2021) [52] | Metformin inhibited osteoclastogenesis, inflammatory response, and angiogenesis in vitro. |
Clinical | |
Lu et al. (2019) [63] | Combination of a COX-2 inhibitor and metformin reduced admission rates of patients with RA and DM compared to COX-2 inhibitor therapy alone. |
Naffaa et al. (2020) [64] | Adherence to metformin treatment was associated with reduced risk of incident RA in women. |
Abdallah et al. (2021) [65] | Patients with RA treated with adjunctive metformin showed a greater rate of achieving ACR20 response after 12 weeks in a randomized, placebo-controlled trial. |
RA, rheumatoid arthritis; CAIA, collagen-antibody induced arthritis; Treg, regulatory T; CIA, collagen-induced arthritis; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cell; FGF21, fibroblast growth factor 21; FLS, fibroblast like synoviocyte; IL-6, interleukin 6; COX-2, cyclooxygenase-2; DM, diabetes mellitus; ACR20, American College of Rheumatology 20.
Study | Results |
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Preclinical | |
Wang et al. (2019) [94] | Metformin inhibited IL-1β-induced oxidative stress and mitochondrial dysfunction in mouse chondrocytes via the activation of SIRT3-mediated PINK1/Parkin-dependent mitophagy. |
Park et al. (2019) [100] | Metformin-treated Ad-hMSCs inhibited inflammatory and catabolic process of IL-1β-stimulated OA chondrocytes and revealed antinociceptive and chondroprotective effects in MIA-induced OA rats compared to metformin-untreated Ad-hMSCs. |
Schadler et al. (2020) [85] | Metformin-treated human OA chondrocytes had reduced gene expressions of catabolic markers, such as ADAMTS5 and MMP1, compared to untreated control samples. |
Li et al. (2020) [86] | Metformin attenuated cartilage degradation and modulated pain behavior in a DMM-induced OA mouse model as well as reduced MMP-13 expression and increased type II collagen expression in IL-1β-stimulated mouse chondrocytes. |
Feng et al. (2020) [87] | Metformin reduced cartilage degradation and aging in a DMM-induced OA mouse model and IL-1β-stimulated mouse cartilage explants. |
Li et al. (2020) [88] | Metformin reduced cartilage degradation, synovitis, and osteophyte formation and attenuated pain in a DMM-induced OA mouse model and inhibited catabolic markers and enhanced anabolic markers in TNF-α or IL-1β-stimulated mouse chondrocytes. These effects were abolished in AMPKα1 KO mice. |
Wang et al. (2020) [95] | Metformin attenuated cartilage degradation, activated autophagy, and inhibited apoptosis in a DMM-induced OA mouse model and IL-1β-stimulated mouse chondrocytes via the AMPKα2-SIRT1 pathway. |
Dawood et al. (2020) [98] | Induction of diabetes caused articular cartilage loss in rats, which was inhibited by metformin treatment. Metformin inhibited hyperglycemia and markers associated with inflammation and oxidative stress. |
Zhang et al. (2020) [99] | Metformin suppressed ECM catabolism, inflammation, and apoptosis in IL-1β-stimulated mouse chondrocytes. |
Na et al. (2021) [96] | Metformin reduced pain and cartilage degradation in MIA-induced OA rats and inhibited apoptosis and activated autophagy in IL-1β-stimulated human OA chondrocytes. |
Clinical | |
Barnett et al. (2017) [71] | Exposure to metformin treatment had no association with OA risk in patients with type 2 diabetes. |
Lu et al. (2018) [72] | Combination of a COX-2 inhibitor and metformin reduced rate of joint replacement in patients with OA and DM compared to COX-2 inhibitor therapy alone. |
Wang et al. (2019) [74] | Metformin use was associated with less knee cartilage volume loss over 4 years in obese people with OA. |
OA, osteoarthritis; IL-1β, interleukin-1β; SIRT, sirtuin; PINK1, phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1; Ad-hMSC, adipose tissue-derived human mesenchymal stem cell; MIA, modosodium iodoacetate; ADAMTS5, a disintegrin and metalloproteinase with thrombospondin motifs 5; MMP, matrix metalloproteinase; DMM, destabilization of medial meniscus; TNF-α; tumor necrosis factor-α; AMPK, AMP-activated kinase; KO, knockout; ECM, extracellular matrix; COX-2, cyclooxygenase-2; DM, diabetes mellitus.
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