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, PGE2, IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway c-Jun NH2-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 PGE2, and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, and PGE2 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.

IntroductionAdiponectin is an adipokine that regulates energy metabolism and insulin sensitivity, but recent studies have pointed also to a role in inflammation and arthritis. The purpose of the present study was to investigate the association and effects of adiponectin on inflammation and cartilage destruction in osteoarthritis (OA).MethodsCartilage and blood samples were collected from 35 male OA patients undergoing total knee replacement surgery. Preoperative radiographs were evaluated using Ahlbäck classification criteria for knee OA. Circulating concentrations of adiponectin and biomarkers of OA, that is, cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase 3 (MMP-3), were measured. Cartilage samples obtained at the time of surgery were cultured ex vivo, and the levels of adiponectin, nitric oxide (NO), IL-6, MMP-1 and MMP-3 were determined in the culture media. In addition, the effects of adiponectin on the production of NO, IL-6, MMP-1 and MMP-3 were studied in cartilage and in primary chondrocyte cultures.ResultsPlasma adiponectin levels and adiponectin released from OA cartilage were higher in patients with the radiologically most severe OA (Ahlbäck grades 4 and 5) than in patients with less severe disease (Ahlbäck grades 1 to 3). Plasma adiponectin concentrations correlated positively with biomarkers of OA, that is, COMP (r = 0.55, P = 0.001) and MMP-3 (r = 0.34, P = 0.046). Adiponectin was released by OA cartilage ex vivo, and it correlated positively with production of NO (r = 0.43, P = 0.012), IL-6 (r = 0.42, P = 0.018) and MMP-3 (r = 0.34, P = 0.051). Furthermore, adiponectin enhanced production of NO, IL-6, MMP-1 and MMP-3 in OA cartilage and in primary chondrocytes in vitro in a mitogen-activated protein kinase (MAPK)-dependent manner.ConclusionsThe findings of this study show that adiponectin is associated with, and possibly mediates, cartilage destruction in OA.

Osteoarthritis (OA) is the most common cause of musculoskeletal disability and pain in the world. The current drug treatment for OA is symptom relieving, and there is an urgent need for treatments that could retard, prevent or repair cartilage destruction in OA. Obesity is a major risk factor for OA. Traditionally, it has been thought to contribute to the development of OA by increasing the load on weight-bearing joints. However, this appears to be an over-simplification, because obesity is also linked to OA in the hand and finger joints. Recent studies have shown that adipocytokine leptin is a possible link between obesity and OA: Leptin levels in synovial fluid are increased in obese patients, leptin receptor (Ob-R) is expressed in cartilage, and leptin induces the production of matrix metalloproteinases (MMPs), pro-inflammatory mediators and nitric oxide (NO) in chondrocytes. Furthermore, according to the very recent findings, not only leptin levels in the joint but also leptin sensitivity in the cartilage are enhanced in obese OA patients. The findings supporting leptin as a causative link between obesity and OA offer leptin as a potential target to the development of disease-modifying drugs for osteoarthritis (DMOAD), especially for obese patients.