Metformin limits osteoarthritis development and progression through activation of AMPK signalling

Abstract

ObjectivesIn this study, we aim to determine the effect of metformin on osteoarthritis (OA) development and progression.MethodsDestabilisation of the medial meniscus (DMM) surgery was performed in 10-week-old wild type and AMP-activated protein kinase (AMPK)α1 knockout (KO) mice. Metformin (4 mg/day in drinking water) was given, commencing either 2 weeks before or 2 weeks after DMM surgery. Mice were sacrificed 6 and 12 weeks after DMM surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology and pain-related behaviour tests. AMPKα1 (catalytic alpha subunit of AMPK) expression was examined by immunohistochemistry and immunofluorescence analyses. The OA phenotype was also determined by μCT and MRI in non-human primates.ResultsMetformin upregulated phosphorylated and total AMPK expression in articular cartilage tissue. Mild and more severe cartilage degeneration was observed at 6 and 12 weeks after DMM surgery, evidenced by markedly increased Osteoarthritis Research Society International scores, as well as reduced cartilage areas. The administration of metformin, commencing either before or after DMM surgery, caused significant reduction in cartilage degradation. Prominent synovial hyperplasia and osteophyte formation were observed at both 6 and 12 weeks after DMM surgery; these were significantly inhibited by treatment with metformin either before or after DMM surgery. The protective effects of metformin on OA development were not observed in AMPKα1 KO mice, suggesting that the chondroprotective effect of metformin is mediated by AMPK signalling. In addition, we demonstrated that treatment with metformin could also protect from OA progression in a partial medial meniscectomy animal model in non-human primates.ConclusionsThe present study suggests that metformin, administered shortly after joint injury, can limit OA development and progression in injury-induced OA animal models.

Metformin Attenuates Monosodium-Iodoacetate-Induced Osteoarthritis via Regulation of Pain Mediators and the Autophagy–Lysosomal Pathway

“…A recent study showed the chondroprotective effect of metformin in injury-induced OA animal models [23], which is consistent with our result. OA can have multiple causes, and metformin has a tentative effect when OA has mechanical causes such as meniscus surgery.…”

“…The antiarthritic and anti-inflammatory effects of metformin have been reported [12,13]. It has been shown that metformin has a therapeutic effect on OA animal models and cohort studies [14,18,23]. The present study confirmed the therapeutic effect of metformin in rats with MIA-induced OA and, thus, its potential clinical use on OA patients.…”

Metformin extends the lifespan of iMSUD mice by rescuing physiologic dysfunction and modulating mechanisms of mTORC1 activation

“…4A, Figure S4). Metformin has been shown to promote mitochondrial metabolism via regulation of redox state (33)(34)(35)(36)(37), activation of AMPK (38)(39)(40)(41)(42) and increased the production of lactate (43)(44)(45)(46). Here, metformin was unable to restore intra-tissue lactate or TCA metabolite levels in iMSUD mice unlike in wild type mice, suggesting that BCKDH function is required for metformin action (Fig.…”

Metformin: A Potential Therapeutic Tool for Rheumatologists

“…Osteoarthritis limited development and delayed progression in a DMM murine model, not in an AMPK/α1 knockout DMM mice [33] Chondroprotection in a partial medial meniscectomy model of non-human primates [33] Reduced knee osteoarthritis progression in obese patients [34] Decreased risk of joint replacement surgery by 25% over 10 years [35] Improvement of osteoarthritis-related pain on a DMM OA mouse model [36] Chondroprotective and antinociceptive effect of intravenous [i.v.] administration of metformin-stimulated Ad-hMSCs [37]…”

“…Data on this topic are poor and even controversial. However, a very recent investigation [33] demonstrated that metformin administration shortly after joint injury in an OA murine model of destabilization of the medial meniscus (DMM) limited OA development and delayed OA progression, even relieving pain sensitivity. In addition, these benefits were lost in an OA model of AMPK α1 knockout (KO) and DMM mice, thus suggesting that the chondroprotective effect of the drug was mediated by upregulating AMPK α1 expression.…”