Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production

Mediators Inflamm. 2009;2009:345838. doi: 10.1155/2009/345838. Epub 2009 Aug 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cartilage / metabolism
  • Cartilage / pathology*
  • Dinoprostone / metabolism*
  • Humans
  • Inflammation*
  • Interleukin-6 / metabolism*
  • Interleukin-8 / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Leptin / metabolism*
  • MAP Kinase Signaling System
  • Middle Aged
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology*

Substances

  • Interleukin-6
  • Interleukin-8
  • Leptin
  • NF-kappa B
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • JNK Mitogen-Activated Protein Kinases
  • Dinoprostone