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Adipocytokines in Synovial Fluid
To the Editor: Adipocytes secrete several highly active molecules including leptin, adiponectin, and resistin. These substances, collectively known as adipocytokines, may function as signaling molecules that influence insulin sensitivity of peripheral tissues.1
Adiponectin belongs to the C1q/tumor necrosis factor- molecular superfamily and is regarded as a novel molecule coupling energy balance and metabolism with immune function and defense.2 Resistin was initially described as an adipocyte-derived mediator of hepatic insulin resistance and is regulated by peroxisome proliferator-activated receptor gamma and CCAAT-enhancer binding proteins.3 Because activation of the local complement system is involved in the pathogenesis of rheumatoid athritis (RA)4 and because cytokine production has been detected in the infrapatellar fat pad,5 we investigated whether adiponectin and resistin can be detected in synovial fluid of the knee and whether their presence differs in patients with RA vs those with osteoarthritis (OA).
Methods
We obtained synovial fluid from 52 outpatients (39 women, 13 men) with RA (n = 24) and OA (n = 28). Synovial concentrations of adiponectin and resistin were measured by enzyme-linked immunosorbent assay (ELISA) according to the protocol provided by the manufacturer (human adiponectin ELISA kit, Biocat, Heidelberg, Germany; human resistin ELISA kit, BioVendor, Brno, Czech Republic).
Results
Patients with RA and OA were not significantly different in terms of age (mean [SD], 67.4 [8.8] and 73.9 [8.1] years, respectively) and female sex (87.5% and 64.3%, respectively). Patients with OA had a significantly higher average body mass index (mean [SD], 31.1 [4.9]) than patients with RA (27.8 [5.7], P = .006).
Of the patients with RA, 14 were receiving steroids and 9 received immunosuppressive therapy. None of the patients with OA had been treated with disease-modifying or immunosuppressive therapies. Erythrocyte sedimentation rate (ESR) was significantly higher in patients with RA (31 mm and 61 mm in the first and second hours, respectively, Westergren method) than in those with OA (14 and 36 mm, respectively) (P = .03). Similarily, mean (SD) levels of C-reactive protein (CRP) were significantly higher in patients with RA (21.8 [19.7] mg/L) than in those with OA (6.6 [4.9] mg/L) (P = .03).
Synovial fluid concentrations of adiponectin were significantly higher in patients with RA than in those with OA (mean [SD], 2.2 [2.7] µg/mL vs 1.1 [0.9] µg/mL, respectively; P = .03), as were concentrations of resistin (mean [SD], 58.9 [74.6] ng/mL vs 6.5 [12.7] ng/mL; P<.001). For patients with both RA and OA we found a significant positive correlation between resistin levels and ESR (Kendall-Tau  test: P = .003 and P = .01, respectively) and with levels of CRP (Kendall-Tau test: P = .005 and p = .003, respectively).
In contrast, however, correlations were not statistically significant between levels of adiponectin and ESR (Kendall-Tau test: P = .70) or levels of CRP (Kendall-Tau test: P = .30) in patients with RA. On the other hand, patients with OA did have a positive correlation (P = .003) of adiponectin levels with CRP levels. There were nearly significant correlations, across the entire sample, between body mass index and levels of adiponectin (r = 0.246, P = .08) and resistin (r = 0.245, P = .07).
Comment
We found that the adipocytokines resistin and adiponectin are present in synovial fluid of patients with both RA and OA. In patients with RA, however, synovial resistin levels were approximately 10 times higher than in those with OA. Furthermore, levels of resistin are positively correlated with systemic markers of inflammation such as ESR and CRP. Levels of adiponectin also were elevated in the synovial fluid of patients with RA, but to a much lesser extent than were levels of resistin.
Although little is known about the regulation of adipocytokines and their impact on the pathophysiology of diseases, they are linked to inflammatory and metabolic pathways. Resistin was originally called FIZZ1 (found in inflammatory zone-1) and is regulated by the TH2 cell cytokines interleukin 4 and interleukin 13 via a number of intermediaries.6 In this context, resistin has been discussed as a link between obesity and inflammatory diseases.7 Adiponectin, on the other hand, is a signaling molecule with metabolic effects (influencing insulin sensitivity and lipid metabolism) rather than proinflammatory effects.2
Our data support the hypothesis that resistin and adiponectin are involved in inflammatory and metabolic pathways in human rheumatologic disease. These data also suggest a possible metabolic role of adipose tissue in arthritis.
Funding/Support: This work was supported by EULAR-AMGEN Young Investigator Award 2003 and by grants MU 1383/3-3 and SCA 789/2-3 from the German Research Association.
Acknowledgment: We thank technicians Kerstin Winkler, Wiebke Ballhorn, Birgit Riepl, and Sigrun Ammon for their technical assistance.
Andreas Schäffler, MD;
Angela Ehling, MD;
Elena Neumann, PhD;
Hans Herfarth, MD;
Ingo Tarner, MD;
Jürgen Schölmerich, MD;
Ulf Müller-Ladner, MD
Department of Internal Medicine I
University of Regensburg
Regensburg, Germany
Steffen Gay, MD
Center for Experimental Rheumatology
University of Zurich
Zurich, Switzerland
1. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med. 2002;8:731-737.
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2. Ukkola O, Santaniemi M. Adiponectin: a link between excess adiposity and associated comorbidities? J Mol Med. 2002;80:696-702.
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3. Patel L, Buckels AC, Kinghorn IJ, et al. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun. 2003;300:472-476.
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4. Grant EP, Picarella D, Burwell T, et al. Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis. J Exp Med. 2002;196:1461-1471.
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5. Ushiyama T, Chano T, Inoue K, Matsusue Y. Cytokine production in the infrapatellar fat pad: another source of cytokines in knee synovial fluids. Ann Rheum Dis. 2003;62:108-112.
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6. Stutz AM, Pickart LA, Trifilieff A, Baumruker T, Prieschl-Strassmayr E, Woisetschlager M. The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone-1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer binding protein-dependent mechanism. J Immunol. 2003;170:1789-1796.
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7. Gomez-Ambrosi J, Fruhbeck G. Do resistin and resistin-like molecules link obesity to inflammatory diseases? Ann Intern Med. 2001;135:306-307.
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Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.
JAMA. 2003;290:1709-1710.
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