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MARIA BOKAREWA, MAGNUS ABRAHAMSON, NIKOLAY LEVSHIN, ARNE EGESTEN, ANDERS GRUBB, LEIF DAHLBERG, and ANDREJ TARKOWSKI
ABSTRACT. Methods. Levels of CysC and SAA and antibodies against these proteins were assessed in the paired blood and synovial fluid (SF) samples of 90 patients with rheumatoid arthritis (RA). Age and sex matched individuals having normal iohexol clearance (n = 90) and SF following joint trauma (n = 40) were used as controls. In vitro experiments included assessment of interaction between CysC and SAA by ELISA and the influence of CysC on SAA functions. Results. A pilot screening for cystatins C, E, and F in blood and SF of patients with RA found CysC to be by far the predominant extracellular cystatin. Circulating CysC levels were significantly lower in patients with RA compared to the matched controls (0.81 ± 0.03 vs 1.01 ± 0.03 mg/l; p = 0.05). These low CysC levels could not be explained by the presence of anti-CysC antibodies in patients with RA. In contrast, concentrations of CysC that accumulated in the inflamed SF were significantly greater in patients with erosive RA (1.66 ± 0.08 mg/l) compared to nonerosive RA (1.36 ± 0.06 mg/l; p = 0.003) and controls (1.18 ± 0.03 mg/l; p = 0.043). In vitro studies showed direct binding of CysC to SAA. CysC/SAA binding impaired proinflammatory effects of SAA, reducing its ability to trigger expression of proinflammatory cytokines. Conclusion. Our study shows a relative deficiency of circulating CysC during systemic inflammation in RA. Physical interaction between CysC and the acute-phase protein SAA (1) provides an explanation for CysC deficiency; and (2) suggests that CysC is regulating inflammatory responses. We hypothesize that decreased systemic CysC levels predispose to accelerated atherosclerosis and development of amyloidosis in patients with RA. (J Rheumatol 2007;34:1293-301) Key Indexing Terms:
CYSTATIN C
From the Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborg; Department of Clinical Chemistry, University Hospital, Lund; and Department of Orthopaedics, University Hospital UMAS, University of Lund, Malmö, Sweden. Supported by Göteborg Medical Society, Swedish Association against Rheumatism, King Gustaf V's Foundation, Swedish Medical Research Council, Nanna Svartz Foundation, National Inflammation Network, EU Foundation (QLRT-2001-01250), and the University of Göteborg. M. Bokarewa, MD, Assistant Professor; N. Levshin, MD; A. Tarkowski, MD, Professor, Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital; M. Abrahamson, MD, Assistant Professor; A. Egesten, MD, Assistant Professor; A. Grubb, MD, Professor, Department of Clinical Chemistry, University Hospital; L. Dahlberg, MD, Assistant Professor, Department of Orthopaedics, University Hospital UMAS. Address reprint requests to Dr. M. Bokarewa, Department of Rheumatology, Guldhedsgatan 10, S-413 46 Göteborg, Sweden. E-mail: maria.bokarewa@rheuma.gu.se Accepted for publication February 2, 2007. |
