Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production.
Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO, PGE(2), IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathway c-Jun NH(2)-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, and PGE(2), and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, and PGE(2) production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.
Vuolteenaho
Katriina
K
The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, 33014 University of Tampere, Tampere, Finland.
Koskinen
Anna
A
Kukkonen
Meiju
M
Nieminen
Riina
R
Päivärinta
Unto
U
Moilanen
Teemu
T
Moilanen
Eeva
E
D000368:Aged; D000369:Aged, 80 and over; D002356:Cartilage / Q000378:metabolism / Q000473:pathology*; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology*
D015850:Interleukin-6; D016209:Interleukin-8; D020738:Leptin; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; D015232:Dinoprostone
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