Metformin pretreatment suppresses alterations to the articular cartilage ultrastructure and knee joint tissue damage secondary to type 2 diabetes mellitus in rats

Dawood, Amal F; Alzamil, Norah M; Ebrahim, Hasnaa Ali; Kader, Dina H Abdel; Kamar, Samaa S; Haidara, Mohamed A

doi:10.1080/01913123.2020.1762815

Cited by 7 publications

(10 citation statements)

References 28 publications

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“…Met alone had no effect on OA score, and the addition of Met was unable to completely rescue the detrimental effects of Rap-induced hyperglycemia. This is in contrast to previous studies that showed Met protected against secondary OA in mice and rhesus monkeys 24 and attenuated hyperglycemia-induced OA in mice 48 . One major difference between studies, besides species, is metformin dose.…”

Section: Discussioncontrasting

confidence: 99%

“…The glucose lowering effects of Met are in line with previous studies where Met alleviated Rap-induced glucose intolerance only in female mice (37). However, our OA pathology findings are in contrast to previous studies that showed Met attenuated hyperglycemia-induced OA in mice (55). In our study, medial tibial proteoglycan loss was correlated with plasma glucose, and we propose that Rap-induced hyperglycemia may have contributed to worsened OA following dietary Rap treatment.…”

Section: Discussionsupporting

confidence: 90%

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Rapamycin induced hyperglycemia is associated with exacerbated age-related osteoarthritis

Minton

Elliehausen

Javors

et al. 2021

Preprint

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Objective: Determine if mechanistic target of rapamycin (mTOR) inhibition and/or AMP-activated protein kinase (AMPK) activation can modify primary osteoarthritis (OA). Design: Dunkin-Hartley guinea pigs develop mild primary OA pathology by 5-months of age that progresses to moderate OA by 8-months of age. At 5-months, guinea pigs were fed either a control diet (n=8) or a diet enriched with the mTOR-inhibitor rapamycin (Rap, 14ppm, n=8), the AMPK-activator metformin (Met, 1000ppm, n=8), or the combination of rapamycin plus metformin (Rap+Met, 14+1000ppm, n=7) for 12 weeks. Knee joints were evaluated by OARSI scoring, micro-computed tomography, and immunohistochemistry. Glenohumeral articular cartilage was collected for western blotting. Results: Dietary treatment with Rap and Rap+Met decreased body weight compared to control. Rap and Rap+Met inhibited articular cartilage mTORC1 but not mTORC2 signaling. Rap+Met, but not Rap or Met alone, stimulated AMPK. Despite lower body weight and articular cartilage mTORC1 inhibition, Rap and Rap+Met treated guinea pigs had greater OA severity in the medial tibial plateau due to articular cartilage structural damage and/or proteoglycan loss. Rap and Rap+Met increased plasma glucose compared to control. Plasma glucose concentration was positively correlated with OA pathology. Conclusions: This is the first study to show that Rap induced increase in plasma glucose was associated with greater OA severity. Further, articular cartilage mTORC1 inhibition and bodyweight reduction by dietary Rap were insufficient to protect against primary OA during the prevailing hyperglycemia.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 90%

Rapamycin induced hyperglycemia is associated with exacerbated age-related osteoarthritis

Minton

Elliehausen

Javors

et al. 2021

Preprint

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“…Therefore, decreasing synovitis might prevent or delay OA progression. Metformin reduced joint and systemic inflammation by inhibiting NF-κB, which was involved in inflammatory OA cascades [ 88 , 98 , 99 ]. In addition to reducing synovitis and structural damage, metformin also decreased pain levels in OA animal models [ 86 , 88 , 96 ].…”

Section: Therapeutic Effects Of Metformin In Osteoarthritismentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

Metformin and its therapeutic applications in autoimmune inflammatory rheumatic disease

Kim

Choe

Park

2022

Korean J Intern Med

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Metformin is a first-line therapeutic agent for type 2 diabetes. Apart from its glucose- lowering effect, metformin is attracting interest regarding possible therapeutic benefits in various other conditions. As metformin regulates cell metabolism, proliferation, growth, and autophagy, it may also modulate immune cell functions. Given that metformin acts on multiple intracellular signaling pathways, including adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation, and that AMPK and its downstream intracellular signaling control the activation and differentiation of T and B cells and inflammatory responses, metformin may exert immunomodulatory and anti- inflammatory effects. The efficacy of metformin has been investigated in preclinical and clinical studies on rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Sjögren’s syndrome, scleroderma, ankylosing spondylitis, and gout. In this review, we discuss the potential mechanisms through which metformin exerts its therapeutic effects in these diseases, focusing particularly on rheumatoid arthritis and osteoarthritis.

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“…Metformin promoted activation of AMPK, resulting in NF-κ B inhibition in IL-1β-induced ATDC5 cells and protected chondrocytes [56]. Articular cartilage change in type 2 diabetes can be protected by metformin via an anti-inflammatory effect in a mouse model [57]. Administration of metformin after DMM surgery restricted OA development and progression via AMPK activation [58].…”

Section: Osteoarthritismentioning

confidence: 99%

Metformin as a Treatment Strategy for Sjögren’s Syndrome

Kim

Park

2021

IJMS

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Sjögren’s syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5’ adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.

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Metformin pretreatment suppresses alterations to the articular cartilage ultrastructure and knee joint tissue damage secondary to type 2 diabetes mellitus in rats

Cited by 7 publications

References 28 publications

Rapamycin induced hyperglycemia is associated with exacerbated age-related osteoarthritis

Rapamycin induced hyperglycemia is associated with exacerbated age-related osteoarthritis

Metformin and its therapeutic applications in autoimmune inflammatory rheumatic disease

Metformin as a Treatment Strategy for Sjögren’s Syndrome

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