Patients with Rheumatoid Arthritis Have an Altered Circulatory Aggrecan Profile

Overview

Journal BMC Musculoskelet Disord

Publisher Biomed Central

Specialties Orthopedics
Physiology

Date 2008 May 30

PMID 18507823

Citations 7

Authors

Jean C Rousseau

Eren U Sumer

Gert Hein

Bodil C Sondergaard

Suzi H Madsen

Christian Pedersen

Thomas Neumann

Andreas Mueller

Per Qvist

Pierre Delmas

Morten A Karsdal

Affiliations

Soon will be listed here.

Abstract

Background: Rheumatoid arthritis (RA) is a chronic auto-immune disease with extensive articular cartilage destruction. Aggrecan depletion, mediated by aggrecanases is one of the first signs of early cartilage erosion. We investigated, whether measurement of aggrecan and fragments thereof in serum, could be used as biomarkers for joint-disease in RA patients and furthermore characterized the fragments found in the circulation.

Methods: The study consisted of 38 patients, 12 males (62.2 +/- 16.0 years) and 26 females (59.8 +/- 20.7 years) diagnosed with RA: 41.5 +/- 27.5 mm/h erythrocyte sedimentation rate (ESR), 38.4 +/- 34.7 mg/ml C-reactive protein (CRP) and 4.8 +/- 1.7 disease activity score (DAS) and 108 healthy age-matched controls. Aggrecan levels were measured using two immunoassays, i.e. the (374)ARGSVI-G2 sandwich ELISA measuring aggrecanase-mediated aggrecan degradation and the G1/G2 sandwich assay, detecting aggrecan molecules containing G1 and/or G2 (total aggrecan) We further characterized serum samples by western blots, by using monoclonal antibodies F-78, binding to G1 and G2, or by BC-3, detecting the aggrecanase-generated N-terminal 374ARGSVI neo-epitope.

Results: Total aggrecan levels in RA patients were significantly decreased from 824.8 +/- 31 ng/ml in healthy controls to 570.5 +/- 30 ng/ml (31% decrease, P < 0.0001), as measured by the G1/G2 ELISA. Western blot analysis with F-78 showed one strong band at 10 kDa, and weaker bands at 25 and 45 kDa in both healthy controls and RA patients. In contrast, staining for aggrecanase-activity revealed only one strong band in RA patients of 45 kDa.

Conclusion: This is the first study, which characterizes different aggrecan fragments in human serum. The data strongly suggests that total aggrecan levels, i.e. aggrecan molecules containing G1 and/or G2 are lower in RA patients, and that RA patients have at least one specific subpopulation of aggrecan fragments, namely aggrecanse generated 374ARGSVI fragments. Further clinical studies are needed to investigate the potential of G1/G2 as a structure-related biochemical marker in destructive joint-diseases.

Citing Articles

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Aggrecan Turnover in Women with Rheumatoid Arthritis Treated with TNF-α Inhibitors.

Szeremeta A, Jura-Poltorak A, Zon-Giebel A, Kopec-Medrek M, Kucharz E, Olczyk K J Clin Med. 2020; 9(5).

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Mesenchymal Stem Cell-Conditioned Medium Reduces Disease Severity and Immune Responses in Inflammatory Arthritis.

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Matrix metalloproteinase-dependent turnover of cartilage, synovial membrane, and connective tissue is elevated in rats with collagen induced arthritis.

Siebuhr A, Wang J, Karsdal M, Bay-Jensen A, Y J, Q Z J Transl Med. 2012; 10:195.

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References

Shanahan J, Clair W . Tumor necrosis factor-alpha blockade: a novel therapy for rheumatic disease. Clin Immunol. 2002; 103(3 Pt 1):231-42. DOI: 10.1006/clim.2002.5191. View

Flugge L, Petillo P . Towards a molecular understanding of arthritis. Chem Biol. 1999; 6(6):R157-66. DOI: 10.1016/S1074-5521(99)80043-X. View

Goldring M . The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res. 2000; 40(1):1-11. DOI: 10.3109/03008209909005273. View

Sandy J, Flannery C, Neame P, Lohmander L . The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain. J Clin Invest. 1992; 89(5):1512-6. PMC: 443022. DOI: 10.1172/JCI115742. View

Garnero P, Rousseau J, Delmas P . Molecular basis and clinical use of biochemical markers of bone, cartilage, and synovium in joint diseases. Arthritis Rheum. 2000; 43(5):953-68. DOI: 10.1002/1529-0131(200005)43:5<953::AID-ANR1>3.0.CO;2-Q. View

Ishikawa T, Nishigaki F, Christgau S, Noto T, Mo J, From N . Cartilage destruction in collagen induced arthritis assessed with a new biochemical marker for collagen type II C-telopeptide fragments. J Rheumatol. 2004; 31(6):1174-9. View

Posthumus M, Limburg P, Westra J, van Leeuwen M, van Rijswijk M . Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods with and without progression of radiological damage in patients with early rheumatoid arthritis. Clin Exp Rheumatol. 2003; 21(4):465-72. View

Garnero P, Ayral X, Rousseau J, Christgau S, Sandell L, Dougados M . Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis. Arthritis Rheum. 2002; 46(10):2613-24. DOI: 10.1002/art.10576. View

Aigner T, McKenna L . Molecular pathology and pathobiology of osteoarthritic cartilage. Cell Mol Life Sci. 2002; 59(1):5-18. PMC: 11337501. DOI: 10.1007/s00018-002-8400-3. View

10.

Sztrolovics R, White R, Roughley P, Mort J . The mechanism of aggrecan release from cartilage differs with tissue origin and the agent used to stimulate catabolism. Biochem J. 2002; 362(Pt 2):465-72. PMC: 1222408. DOI: 10.1042/0264-6021:3620465. View

11.

Chockalingam P, Zeng W, Morris E, Flannery C . Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS-4 (aggrecanase 1) or ADAMTS-5 (aggrecanase 2). Arthritis Rheum. 2004; 50(9):2839-48. DOI: 10.1002/art.20496. View

12.

Sugimoto K, Iizawa T, Harada H, Yamada K, Katsumata M, Takahashi M . Cartilage degradation independent of MMP/aggrecanases. Osteoarthritis Cartilage. 2004; 12(12):1006-14. DOI: 10.1016/j.joca.2004.09.003. View

13.

Zink A, Listing J, Klindworth C, Zeidler H . The national database of the German Collaborative Arthritis Centres: I. Structure, aims, and patients. Ann Rheum Dis. 2001; 60(3):199-206. PMC: 1753589. DOI: 10.1136/ard.60.3.199. View

14.

Struglics A, Larsson S, Pratta M, Kumar S, Lark M, Lohmander L . Human osteoarthritis synovial fluid and joint cartilage contain both aggrecanase- and matrix metalloproteinase-generated aggrecan fragments. Osteoarthritis Cartilage. 2005; 14(2):101-13. DOI: 10.1016/j.joca.2005.07.018. View

15.

Firestein G . Evolving concepts of rheumatoid arthritis. Nature. 2003; 423(6937):356-61. DOI: 10.1038/nature01661. View

16.

Ravaud P, Giraudeau B, Auleley G, Drape J, Rousselin B, Paolozzi L . Variability in knee radiographing: implication for definition of radiological progression in medial knee osteoarthritis. Ann Rheum Dis. 1999; 57(10):624-9. PMC: 1752490. DOI: 10.1136/ard.57.10.624. View

17.

Fosang A, Last K, Maciewicz R . Aggrecan is degraded by matrix metalloproteinases in human arthritis. Evidence that matrix metalloproteinase and aggrecanase activities can be independent. J Clin Invest. 1996; 98(10):2292-9. PMC: 507679. DOI: 10.1172/JCI119040. View

18.

Otero M, Goldring M . Cells of the synovium in rheumatoid arthritis. Chondrocytes. Arthritis Res Ther. 2007; 9(5):220. PMC: 2212563. DOI: 10.1186/ar2292. View

19.

Karsdal M, Sumer E, Wulf H, Madsen S, Christiansen C, Fosang A . Induction of increased cAMP levels in articular chondrocytes blocks matrix metalloproteinase-mediated cartilage degradation, but not aggrecanase-mediated cartilage degradation. Arthritis Rheum. 2007; 56(5):1549-58. DOI: 10.1002/art.22599. View

20.

Hardingham T, Fosang A . The structure of aggrecan and its turnover in cartilage. J Rheumatol Suppl. 1995; 43:86-90. View