Objective: The etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP‐activated protein kinase (AMPK) and sirtuin 1 (SIRT‐1), which modulate the mitochondrial biogenesis “master regulator” peroxisome proliferator–activated receptor γ coactivator 1α (PGC‐1α). Moreover, PGC‐1α critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test the hypothesis that mitochondrial biogenesis is deficient in human OA chondrocytes and that this deficiency functionally increases chondrocyte procatabolic responses, which are reversed by activation of the AMPK/SIRT‐1/PGC‐1α pathway.Methods: We assessed the expression and activity (phosphorylation) of AMPKα, SIRT‐1, and PGC‐1α in human knee chondrocytes and human and mouse knee cartilage, and we defined and compared the content and function of mitochondria, including oxidative phosphorylation and expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A [TFAM] and nuclear respiratory factors [NRFs]).Results: Human knee OA chondrocytes had a decreased mitochondrial biogenesis capacity, which was linked to reduced AMPKα activity and decreased expression of SIRT‐1, PGC‐1α, TFAM, NRF‐1, and NRF‐2. Human knee OA and aging mouse knee cartilage had decreased expression of TFAM and ubiquinol–cytochrome c reductase core protein, a subunit of mitochondrial complex III, in situ. Chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced procatabolic responses to interleukin‐1β. Finally, activation of AMPK by A‐769662 increased PGC‐1α expression via SIRT‐1 and reversed impairments in mitochondrial biogenesis, oxidative phosphorylation, and intracellular ATP in human knee OA chondrocytes.Conclusion: Mitochondrial biogenesis is deficient in human OA chondrocytes, and this deficiency promotes chondrocyte procatabolic responses. TFAM‐mediated activation of the AMPK/SIRT‐1/PGC‐1α pathway reverses these effects, suggesting translational potential of pharmacologic AMPK activators to limit OA progression.

Objectives In this study, we aim to determine the effect of metformin on osteoarthritis (OA) development and progression. Methods Destabilisation 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. Results Metformin 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. Conclusions The present study suggests that metformin, administered shortly after joint injury, can limit OA development and progression in injury-induced OA animal models.

Objective AMP-activated protein kinase (AMPK) is metabolic biosensor with anti-inflammatory activities. Gout is commonly associated with excesses in soluble urate and in nutrition, both of which suppress tissue AMPK activity. Gout is driven by macrophage-mediated inflammation transduced partly by NLRP3 inflammasome activation and interleukin (IL)-1β release. Hence, we tested the hypothesis that AMPK activation limits monosodium urate (MSU) crystal-induced inflammation. Methods We studied bone marrow-derived macrophages (BMDMs) from AMPKα1 knockout and wild-type mice, and assessed the selective AMPK pharmacological activator A-769662 and a low concentration (10 nM) of colchicine. We examined phosphorylation (activation) of AMPKα Thr172, NLRP3 mRNA expression, and caspase-1 cleavage and IL-1β maturation using western blot and quantitative RT-PCR approaches. We also assessed subcutaneous murine air pouch inflammatory responses to MSU crystals in vivo. Results MSU crystals suppressed phosphorylation of AMPKα in BMDMs. Knockout of AMPKα1 enhanced, and, conversely, A-769662-inhibited MSU crystal-induced inflammatory responses including IL-1β and CXCL1 release in vitro and in vivo. A-769662 promoted AMPK-dependent macrophage anti-inflammatory M2 polarisation and inhibited NLRP3 gene expression, activation of caspase-1 and IL-1β. Colchicine, at low concentration (10 nM) achieved in gout flare prophylaxis dosing, promoted phosphorylation of AMPKα and macrophage M2 polarisation, and reduced activation of caspase-1 and release of IL-1β and CXCL1 by MSU crystals in BMDMs in vitro. Conclusions AMPK activity limits MSU crystal inflammation in vitro and in vivo, and transduces multiple anti-inflammatory effects of colchicine in macrophages. Targeting increased and sustained AMPK activation in inflammatory cells merits further investigation for enhancing efficacy of prophylaxis and treatment of gouty inflammation.