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To elucidate the mechanisms by which type 2 Diabetes Mellitus (DM2) constitutes a riskfactor for the development and progression of osteoarthritis (OA), this work determined whetherhigh glucose and/or high insulin, the hallmarks of DM2, are capable of activating the transcriptionfactor, Nuclear Factor-κB (NF-κB), which plays a critical role in OA by inducing the expression ofpro-inflammatory and catabolic genes. For this, we analyzed NF-κB activation by measuring thenuclear levels of p65 by western blot. As readouts of NF-κB activity, Interleukin-1β, Tumor NecrosisFactor-α, and inducible nitric oxide synthase (iNOS) expression were analyzed by real time RT-PCRand western blot. Culture of the human chondrocytic cell line, C28-I2, in high glucose (30 mM)increased nuclear NF-κB p65 levels in a time-dependent manner, relative to cells cultured in mediumcontaining 10 mM glucose (regular culture medium). High glucose-induced NF-κB activation wasinhibited by co-treatment with its specific inhibitor, Bay 11-7082, 5 µM. Culture of primary humanchondrocytes under high glucose for 24 h increased IL-1β and TNF-α mRNA levels by 97% (p = 0.0066)and 85% (p = 0.0045), respectively, while iNOS mRNA and protein levels and NO production increasedby 61% (p = 0.0017), 148% (p = 0.0089), and 70% (p = 0.049), respectively, relative to chondrocytesmaintained in 10 mM glucose. Treatment of chondrocytic cells with 100 nM insulin was also sufficientto increase nuclear NF-κB p65 levels, independently of the glucose concentration in the culturemedium. This study shows that hyperglycemia and hyperinsulinemia are independently sufficient toinduce inflammatory responses in human chondrocytes, namely by activating NF-κB. This can be arelevant mechanism by which DM type 2 and other conditions associated with impaired glucose andinsulin homeostasis, like obesity and the metabolic syndrome, contribute to the development andprogression of OA.info:eu-repo/semantics/publishedVersio

Hyperglycemia and Hyperinsulinemia-Like Conditions Independently Induce Inflammatory Responses in Human Chondrocytes