ARTHRITIS & RHEUMATISM Vol. 48, No. 8, August 2003, pp 2163–2172 DOI 10.1002/art.11093 © 2003, American College of Rheumatology Synovial Fluid Exoglycosidases Are Predictors of Rheumatoid Arthritis and Are Effective in Cartilage Glycosaminoglycan Depletion Zsuzsanna Ortutay, 1 Anna Polga ´r, 2 Be ´la Go ¨mo ¨r, 3 Pa ´l Ge ´her, 3 Tama ´s Lakatos, 3 Tibor T. Glant, 4 Renate E. Gay, 5 Steffen Gay, 5 E ´ va Pa ´llinger, 1 Csaba Farkas, 6 E ´ va Farkas, 1 La ´szlo ´ To ´thfalusi, 1 Katalin Kocsis, 1 Andra ´s Falus, 1 and Edit I. Buza ´s 1 Objective. To analyze enzymes involved in joint damage by simultaneous investigation of glycosidases and matrix metalloproteinases (MMPs) in patients with various joint diseases. Methods. Activities of glycosidases ( - D- glucuronidase, -D-N-acetyl-glucosaminidase, -D-N- acetyl-galactosaminidase, -D-galactosidase, and -D- mannosidase) were tested at an acidic pH as well as at the original pH of the synovial fluid (SF) samples in parallel with activities of MMP-1 and MMP-9. Results. Patients with rheumatoid arthritis (RA) were characterized by significantly elevated activities of -D-glucuronidase and -D-N-acetyl-glucosaminidase in SF compared with patients with osteoarthritis, seroneg- ative spondylarthritis, or acute sports injury. To select the best predictor for distinguishing among patient groups, a stepwise logistic regression analysis was per- formed; the strongest association was found to be between RA and - D-glucuronidase/ - D- N-acetyl- glucosaminidase activities (measured at the pH of the SF). Further, a significant correlation was observed between the activity of SF -D-N-acetyl-glucosaminidase and the level of rheumatoid factor. In vitro digestion of human hyaline cartilage samples revealed that the dominant glycosidases, alone or in combination with MMPs, proved to be effective in depleting glycosamino- glycans (GAGs) from cartilage. Conclusion. These results suggest that exoglyco- sidases, which are present in the SF of RA patients, may contribute to the depletion of GAGs from cartilage and thereby facilitate the invasion of synovial cells and their attachment to cartilage in RA. In joint diseases, the major clinical symptoms and disability of patients are caused by an irreversible de- struction of hyaline cartilage. Enzymes capable of de- grading extracellular matrix components (collagen and aggrecan) and concomitantly exposing chondrocytes to a variety of cytotoxic and/or apoptosis-inducing factors are considered to be the major effector molecules in carti- lage degradation. Recently, significant advances have been made in our understanding of joint destruction and the mecha- nism of proteolytic cleavage of cartilage. Active pro- teases are currently implicated in the destructive pro- cesses and include matrix metalloproteinases (MMPs), the ADAM family (1), the ADAM-TS family (2), and serine proteases (elastase, cathepsins, and granzymes) (3–5). Of the 4 groups of MMPs, collagenase (MMP-1 in particular) appears to be responsible for the degradation of interstitial collagens. The gelatinases (including MMP-2 and MMP-9) degrade the denatured form of collagens, thus acting in synergy with MMP-1. The stromelysins (including MMP-3) have a broader sub- strate specificity for non–connective tissue components. Supported by grant T 032134 from the Hungarian Research Foundation OTKA. 1 Zsuzsanna Ortutay, BS, E ´ va Pa ´llinger, MD, E ´ va Farkas, BS, La ´szlo ´ To ´thfalusi, MD, PhD, Katalin Kocsis, MD, PhD, Andra ´s Falus, PhD, Edit I. Buza ´s, MD, PhD: Semmelweis University, Budapest, Hungary; 2 Anna Polga ´r, MD: National Institute of Rheumatology and Physiotherapy, Budapest, Hungary; 3 Be ´la Go ¨mo ¨r, MD, PhD, Pa ´l Ge ´her, MD, PhD, Tama ´s Lakatos, MD: Polyclinic of Hospitaller Brothers of St. John of God, Budapest, Hungary; 4 Tibor T. Glant, MD, PhD: Rush University at Rush–Presbyterian–St. Luke’s Medical Cen- ter, Chicago, Illinois; 5 Renate E. Gay, MD, Steffen Gay, MD: Univer- sity Hospital of Zurich, Zurich, Switzerland; 6 Csaba Farkas, MD: Josa Andra ´s County Hospital, Nyı ´regyha ´za, Hungary. Address correspondence and reprint requests to Edit I. Buza ´s, MD, PhD, Associate Professor, Department of Genetics, Cell and Immunobiology, Semmelweis University, 4 Nagyva ´rad te ´r, H-1089 Budapest, Hungary. E-mail: buzedi@dgci.sote.hu. Submitted for publication November 4, 2002; accepted in revised form April 7, 2003. 2163