Anna Koskinen

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, 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.

Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways

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.

Leptin – A Link between Obesity and Osteoarthritis. Applications for Prevention and Treatment

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.

Resistin as a factor in osteoarthritis: synovial fluid resistin concentrations correlate positively with interleukin 6 and matrix metalloproteinases MMP-1 and MMP-3

Objectives: Resistin is an adipocytokine that has been related to inflammation and insulin resistance. Following knee injury, elevated levels of resistin have been found in synovial fluid (SF) while very little is known about the role of resistin in osteoarthritis (OA). The aim of the present study was to investigate resistin levels in OA joints and to determine if it is associated with inflammatory and catabolic factors in the joints. Method: SF, plasma, and cartilage samples were collected from 88 OA patients undergoing knee replacement surgery. Resistin levels were measured by enzyme-linked immunosorbent assay (ELISA) in SF, plasma, and cartilage culture media. Results: Significant levels of resistin [0.75 (0.67) ng/mL; median (IQR)] were found in SF from OA patients. Resistin correlated positively with interleukin (IL)-6 (r = 0.39, p < 0.001) and with matrix metalloproteinases MMP-1 (r = 0.31, p = 0.004) and MMP-3 (r = 0.24, p = 0.024) in SF. Resistin was also released from cultured OA cartilage and it correlated with resistin levels in SF (r = 0.39, p < 0.001). In addition, resistin levels in plasma correlated positively with those in SF (r = 0.44, p < 0.001). There were no differences in SF or plasma resistin concentrations between females and males or between non-diabetic and diabetic patients, and resistin did not correlate with body mass index (BMI). Conclusions: Resistin is present in OA joints and is released from OA cartilage. Levels of resistin in SF are associated with inflammatory and catabolic factors, suggesting that resistin has a role to play in the pathogenesis of, and as a possible drug target in, OA.

Leptin levels are increased and its negative regulators, SOCS-3 and sOb-R are decreased in obese patients with osteoarthritis: a link between obesity and osteoarthritis

Leptin is a hormone originally discovered in white adipocytes which regulates energy metabolism and appetite. Obese individuals have increased levels of circulating leptin, as compared with their non-obese counterparts, and in mouse models, leptin deficiency causes morbid obesity.1 However, due to the appearance of leptin resistance in the hypothalamus, increased blood levels of leptin in obese subjects fail to induce the expected responses to high leptin, that is, increased energy expenditure, reduced food intake and decreased body weight.2 Leptin resistance has been shown to be mediated by an increased expression of the suppressor of cytokine signalling-3 (SOCS-3).1 ,2 Obesity has been thought to contribute to the development of osteoarthritis (OA) by increasing the load on weight-bearing joints. However, this appears to be an over-simplification, since obesity is also linked to …

YKL-40 as a Novel Factor Associated with Inflammation and Catabolic Mechanisms in Osteoarthritic Joints

YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients (r = 0.37, P = 0.010), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 (r = 0.36, P = 0.014), MMP-3 (r = 0.46, P = 0.001), IL-6 (r = 0.57, P < 0.001), and IL-17 (r = 0.52, P = 0.010) levels. Moreover, IL-6 and IL-17 enhanced YKL-40 production in human primary chondrocyte cultures. The present study introduces YKL-40 as a cartilage-derived factor associated with mediators of inflammation and cartilage destruction involved in the pathogenesis of OA.

188 LEPTIN INDUCES DETRIMENTAL CHANGES IN HUMAN OA CARTILAGE. EFFECTS ON NITRIC OXIDE, PGE2, IL-6 AND IL-8 PRODUCTION

placement. Chondrocytes were isolated by digestion with collagenase and used in primary culture. Cells were stimulated with IL-1β for different times in the presence or absence of CORM-2 (50, 100 or 150 μM). Gene expression was analyzed by realtime PCR. Protein expression was investigated by Western blot method and immunocytochemistry. Aggrecanase activity, MMP protein levels and phosphorylated/total levels of ERK and IκBα were determined by ELISA, and NF-κB activity by the luciferase method. Results: CORM-2 treatment increased cell viability and collagen II and aggrecan protein expression in primary OA chondrocytes. Increased gene expression of collagen II, aggrecan, link protein, Sox-9 and BMP2 was observed. Interestingly, aggrecanase activity was reduced by CORM-2 in a concentration-dependent manner, as well as gene expression and protein levels of MMP1, MMP-3 and MMP-10. Our results also indicate that downregulation of cartilage degradative enzymes by CORM-2 may be mediated by the inhibition of ERK and IκBα phosphorylation, and of NF-κB activation. Conclusions: CO released by CORM-2 enhances matrix components and decreases the production of MMP and aggrecanase activities induced by IL-1β in OA chondrocytes, indicating the potential interest of this class of compounds in cartilage protection.