BackgroundObesity is a risk factor for osteoarthritis (OA). In obese subjects OA develops not only in weight-bearing joints but also in non-weight-bearing joints, suggesting that dysregulated metabolism in obese patients may promote OA onset.As obesity evolves many physiological parameters are dysregulated, including the levels of adipokine hormones such as leptin and adiponectin. For this reason, it has been suggested that adipokine levels in serum and synovial fluid are associated with a worsening of synovial inflammation and OA progression in these patients(1).In vivo and in vitro studies show that high levels of leptin induce the synthesis of metalloproteases involved in cartilage degradation(2). Conversely, dietary-induced weight loss is associated with increased adiponectin serum levels and reduced loss of tibial and femoral cartilage volume, suggesting a protective role of adiponectin in OA.STR/ort mice are an animal model of spontaneous OA characterized by early pathology development (at about 20 weeks) and dysregulated metabolism(3). Notably, these mice have adiponectin serum levels lower than those found in control mouse strains(4).ObjectivesTo evaluate whether adiponectin and leptin serum levels are associated with OA development and/or progression in STR/ort mice.MethodsFirst, we measured the time course of adipokine levels in STR/ort mice before the onset of OA (at 8, 14 and 20 weeks of age), and in age-matched CBA control mice. Then, we calculated the ratio leptin/adiponectin (L/A) in the serum of STR/ort mice during OA progression (at 20, 30 and 40 weeks). Blood samples were collected from caudal vein (time course) or from vena cava at sacrifice, when knee joints were collected, processed for histology and blindly scored according to OARSI and Mankin's methods.ResultsAdiponectin serum levels in STR/ort mice at 8, 14 and 20 weeks were significantly lower than in age-matched CBA mice. Instead, leptin serum levels in STR/ort mice were higher than in CBA strain at 14 and 20 weeks. Consequently, there was a relevant difference in the ratio L/A between the two strains, with greater L/A values in STR/ort mice at 14 and 20 weeks. (Table 1)In STR/ort mice, the ratio L/A tended to further increase between 30 and 20 weeks (1.73±0.16 from 1.28±0.17, respectively), in parallel with the increase in OARSI scores of knee joints (11.1±1.5 vs 8.4±1.3). The histopathological score increased in STR/ort mice even between 30 and 40 weeks, but without a concomitant increase in the ratio L/A.ConclusionsWe show for the first time that leptin serum levels and the ratio L/A in STR/ort mice are higher than in CBA mice, and that the ratio L/A in STR/ort mice increases as their histopathological scores worsen. We suggest that dysregulated levels of these adipokines may be associated or even precede OA development in this animal model.References King L.K. et al. Osteoarthritis and Cartilage, 2015.Bao J.P. et all. Mol Biol Rep. 2010.Uchida K. et al. Experimental Animals, 2009.Giambelli R. et al. Osteoarthtis and Cartilage Volume 2...
Purpose: Adiponectin, an adipokine secreted from adipose tissue into the bloodstream, is involved in the modulation of different metabolic processes including glucose uptake and fatty acid oxidation. This adipokine acts via two receptors, AdipoR1 and AdipoR2, expressed mainly in the skeletal muscle and liver, respectively, but also in chondrocytes. Adiponectin signal transduction by AdipoR1 and AdipoR2 involves the activation of many signaling molecules like Peroxisome proliferatoractivated receptor gamma (PPARg) and 5' AMP-activated protein kinase (AMPK). Unlike other adipokines, whose production is increased with obesity, adiponectin serum levels decrease with increasing weight. The STR/Ort mouse is a model of spontaneous osteoarthritis (OA) that shows a human-like hyperlipidemic condition and is characterized by a very early pathology development. Furthermore, these animals have serum levels of adiponectin much lower than other mouse strains. It was suggested that systemic (plasma) and local (synovial fluid) adipokine levels would be associated with cartilage degeneration and synovial inflammation, linking obesity and adiposity with inflammation and pathology in OA patients. Moreover, a down-regulation of adiponectin receptors was recently reported in human OA chondrocytes. These observations indicate a possible protective role for adiponectin in the development of osteoarthritis. The purpose of our study was to establish a possible relationship between OA development and hypoadiponectinemia in this model. Methods: STR/Ort and CBA mice were recruited at 6 months (26 weeks) of age and euthanized. Serum was obtained from blood samples taken from vena cava at sacrifice, using Microvette® CB 300 capillary tubes (Sarstedt). Knee joints were collected, processed for histology and blindly scored according to both Mankin's and OARSI methods. Adiponectin levels were evaluated from serum samples by a commercially available kit (Bertin Pharma, cat. A05187). Correlation between the OARSI score and adiponectin levels was examined using Spearman's rank correlation test. Results: Adiponectin serum levels in STR/Ort mice at 26 weeks of age were significantly lower compared to CBA mice at the same age (12.5mg/ ml ± 0.65 and 23.9mg/ml ± 0.98 respectively). We observed a significant negative correlation (p ¼ 0.007) between adiponectin levels and weight in STR/Ort mice but not in CBA mice. Among the 6 CBA mice tested, 10 of the 12 knees examined showed no signs of OA (mean OARSI score ¼ 0.3 and Mankin's score ¼ 0.3). Conversely, in the 17 STR/Ort mice only 1 of 34 knees examined showed no signs of OA, while all the other knees showed high level of cartilage damage (mean OARSI score ¼ 14.1 and Mankin's score ¼ 7.9), as revealed in all histopathological parameters evaluated. There was a negative correlation between adiponectin levels and disease severity (as measured by OARSI score), reaching statistical significance (p ¼ 0.04) when considering the less damaged knee. Conclusions: This study, while confirming that adiponectin serum ...
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