Circulating keratan sulfate as a marker of metabolic changes of cartilage proteoglycan in juvenile idiopathic arthritis; influence of growth factors as well as proteolytic and prooxidative agents on aggrecan alterations
- 
            
            
        Katarzyna Winsz-Szczotka
        , Katarzyna Komosińska-Vassev 
Abstract
Background: The aim of this study was to evaluate the plasma keratan sulfate (KS) level as a potential marker of joint damage in children with juvenile idiopathic arthritis (JIA). The influence of growth factors as well as proteolytic and prooxidative agents on aggrecan alterations were evaluated in this study.
Methods: Plasma levels of KS, transforming growth factor β1 (TGF-β1), platelet-derived growth factor BB (PDGF-BB), a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4 and ADAMTS-5), and thiol groups (TG) were quantified in samples obtained from 30 healthy subjects and 30 patients with JIA before and after treatment.
Results: Increased (p<0.01) plasma KS was observed in JIA patients before treatment. Therapy resulted in a decrease in KS level. However, plasma KS level remained higher (p<0.05) than in controls. Increased levels of TGF-β1 (p<0.01) and PDGF-BB (p<0.05) in untreated JIA patients were recorded. Clinical improvement was accompanied by significant decrease in TGF-β1 and PDGF-BB, compared with a pretreatment condition and a control group. The concentrations of proteinases were characterized by different trends of alterations. When the ADAMTS-4 level increased (p<0.01) in the blood of untreated patients, the concentration of ADAMTS-5 was found to be reduced (p<0.0001), compared with controls. JIA treatment resulted in the normalization of ADAMTS-4 level. Plasma TG concentration was decreased only in untreated patients (p<0.05). We have revealed a significant correlation between plasma KS level and ADAMTS-4, TGF-β1, TG, C-reactive protein, and erythrocyte sedimentation rate levels.
Conclusions: Plasma KS level in JIA patients, reflecting the aggrecan structure, indicates that treatment that modifies inflammation simultaneously does not contribute to total regeneration of articular matrix components and signalizes the need for further treatment.
References
1. Eisenstein EM, Berkun Y. Diagnosis and classification of juvenile idiopathic arthritis. J Autoimmun 2014;48–49:31–3.10.1016/j.jaut.2014.01.009Search in Google Scholar PubMed
2. Vidqvist KL, Malin M, Varjolahti-Lehtinen T, Korpela MM. Disease activity of idiopathic juvenile arthritis continues through adolescence despite the use of biologic therapies. Rheumatology (Oxford) 2013;52:1999–2003.10.1093/rheumatology/ket256Search in Google Scholar PubMed
3. Kahn PJ. Juvenile idiopathic arthritis – what the clinician needs to know. Bull Hosp Jt Dis 2013;71:194–9.Search in Google Scholar
4. Winsz-Szczotka K, Komosińska-Vassev K, Kuźnik-Trocha K, Gruenpeter A, Lachór-Motyka I, Olczyk K. Influence of proteolytic-antiproteolytic enzymes and prooxidative-antioxidative factors on proteoglycan alterations in children with juvenile idiopathic arthritis. Clin Biochem 2014;47:829–34.10.1016/j.clinbiochem.2014.01.027Search in Google Scholar PubMed
5. Ravelli A. The time has come to include assessment of radiographic progression in juvenile idiopathic arthritis clinical trials. J Rheumatol 2008;35:553–7.Search in Google Scholar
6. Kamphuis S, Hrafnkelsdóttir K, Klein MR, de Jager W, Haverkamp MH, van Bilsen JH, et al. Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health. Arthritis Res Ther 2006;8:R178.10.1186/ar2088Search in Google Scholar PubMed PubMed Central
7. Hayashi M, Kadomatsu K, Ishiguro N. Keratan sulfate suppresses cartilage damage and ameliorates inflammation in an experimental mice arthritis model. Biochem Biophys Res Commun 2010;401:463–8.10.1016/j.bbrc.2010.09.082Search in Google Scholar PubMed
8. Struglics A, Lohmander LS, Last K, Akikusa J, Allen R, Fosang AJ. Aggrecanase cleavage in juvenile idiopathic arthritis patients is minimally detected in the aggrecan interglobular domain but robust at the aggrecan C-terminus. Arthritis Rheum 2012;64:4151–61.10.1002/art.34665Search in Google Scholar PubMed
9. Wakitani S, Okabe T, Kawaguchi A, Nawata M, Hashimoto Y. Highly sensitive ELISA for determining serum keratan sulphate levels in the diagnosis of OA. Rheumatology (Oxford) 2010;49:57–62.10.1093/rheumatology/kep351Search in Google Scholar PubMed
10. Miller T, Goude MC, McDevitt TC, Temenoff JS. Molecular engineering of glycosaminoglycan chemistry for biomolecule delivery. Acta Biomater 2014;10:1705–19.10.1016/j.actbio.2013.09.039Search in Google Scholar PubMed PubMed Central
11. Funderburgh JL. Keratan sulfate: structure, biosynthesis, and function. Glycobiology 2000;10:951–8.10.1093/glycob/10.10.951Search in Google Scholar PubMed
12. Wakitani S, Nawata M, Kawaguchi A, Okabe T, Takaoka K, Tsuchiya T, et al. Serum keratan sulfate is a promising marker of early articular cartilage breakdown. Rheumatology (Oxford) 2007;46:1652–6.10.1093/rheumatology/kem220Search in Google Scholar PubMed
13. Lin EA, Liu CJ. The role of ADAMTSs in arthritis. Protein Cell 2010;1:33–47.10.1007/s13238-010-0002-5Search in Google Scholar
14. Verma P, Dalal K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem 2011;112:3507–14.10.1002/jcb.23298Search in Google Scholar
15. Fosang AJ, Rogerson FM. Identifying the human aggrecanase. Osteoarthritis Cartilage 2010;18:1109–16.10.1016/j.joca.2010.06.014Search in Google Scholar
16. Nikitovic D, Zafiropoulos A, Katonis P, Tsatsakis A, Theocharis AD, Karamanos NK, et al. Transforming growth factor-beta as a key molecule triggering the expression of versican isoforms v0 and v1, hyaluronan synthase-2 and synthesis of hyaluronan in malignant osteosarcoma cells. IUBMB Life 2006;58:47–53.10.1080/15216540500531713Search in Google Scholar
17. Rosengren S, Corr M, Boyle DL. Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes. Arthritis Res Ther 2010;12:R65.10.1186/ar2981Search in Google Scholar
18. Yamanishi Y, Boyle DL, Clark M, Maki RA, Tortorella MD, Arner EC, et al. Expression and regulation of aggrecanase in arthritis: the role of TGF-beta. J Immunol 2002;168:1405–12.10.4049/jimmunol.168.3.1405Search in Google Scholar
19. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959;82:70–7.10.1016/0003-9861(59)90090-6Search in Google Scholar
20. Bondeson J, Wainwright S, Hughes C, Caterson B. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin Exp Rheumatol 2008;26:139–45.Search in Google Scholar
21. Mor A, Abramson SB, Pillinger MH. The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol 2005;115:118–28.10.1016/j.clim.2004.12.009Search in Google Scholar
22. Arner EC. Aggrecanase-mediated cartilage degradation. Curr Opin Pharmacol 2002;2:322–9.10.1016/S1471-4892(02)00148-0Search in Google Scholar
23. Naito S, Shiomi T, Okada A, Kimura T, Chijiiwa M, Fujita Y, et al. Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage. Pathol Int 2007;57:703–11.10.1111/j.1440-1827.2007.02167.xSearch in Google Scholar PubMed
24. Henrotin Y, Kurz B, Aigner T. Oxygen and reactive oxygen species in cartilage degradation: friends or foes? Osteoarthritis Cartilage 2005;13:643–54.10.1016/j.joca.2005.04.002Search in Google Scholar PubMed
25. Winsz-Szczotka K, Komosińska-Vassev K, Kuźnik-Trocha K, Olczyk K. Antioxidant activity and structural modifications of serum chondroitin sulfate in Graves’ disease. Clin Biochem 2014;47:19–24.10.1016/j.clinbiochem.2013.08.002Search in Google Scholar PubMed
26. Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis 2012;4:269–85.10.1177/1759720X12448454Search in Google Scholar PubMed PubMed Central
27. Song RH, Tortorella MD, Malfait AM, Alston JT, Yang Z, Arner EC, et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum 2007;56:575–85.10.1002/art.22334Search in Google Scholar PubMed
28. Blanco FJ, Rego I, Ruiz-Romero C. The role of mitochondria in osteoarthritis. Nat Rev Rheumatol 2011;7:161–9.10.1038/nrrheum.2010.213Search in Google Scholar PubMed
29. EL-Batouty MF, EL-Lakkany A, Hawas S, EL-Nashar E, Hafez MM, EL-Desoky T, et al. Role of articular cartilage and chondrocyte changes and mononuclear apoptosis in the pathogenesis and strategy of therapy in polyarticular juvenile rheumatoid arthritis. J Med Sci 2003;3:137–56.10.3923/jms.2003.137.156Search in Google Scholar
30. Campion GV, McCrae F, Schnitzer TJ, Lenz ME, Dieppe PA, Thonar EJ. Levels of keratan sulfate in the serum and synovial fluid of patients with osteoarthritis of the knee. Arthritis Rheum 1991;34:1254–9.10.1002/art.1780341008Search in Google Scholar PubMed
©2015 by De Gruyter
Articles in the same Issue
- Frontmatter
- Editorials
- The new and the old of heparin-induced thrombocytopenia
- Biological variation – reliable data is essential
- Biological variation: back to basics
- Review
- Influence of educational, audit and feedback, system based, and incentive and penalty interventions to reduce laboratory test utilization: a systematic review
- Opinion Papers
- Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus?
- Meeting report: present state of molecular genetics in clinical laboratories. Report on the VII European Symposium on Clinical Laboratory and In Vitro Diagnostic Industry in Barcelona
- Genetics and Molecular Diagnostics
- Non-invasive prenatal diagnosis of monogenic disorders: an optimized protocol using MEMO qPCR with miniSTR as internal control
- A novel biosensor-based microarray assay for the visualized detection of CYP2C19 ∗2, ∗3, ∗4 and ∗5 polymorphisms
- General Clinical Chemistry and Laboratory Medicine
- Preanalytical errors: a preliminary approach to the point of view of primary health care givers
- Comparison of Improvacuter™ tubes with BD Vacutainer™ tubes for various hormones in the aspects of stability and influence of gel separators
- Use of quality indicators to compare point-of-care testing errors in a neonatal unit and errors in a STAT central laboratory
- Serological features of antibodies to protamine inducing thrombocytopenia and thrombosis
- Comparison of three different immunoassays in the diagnosis of heparin-induced thrombocytopenia
- How the direct oral anticoagulant apixaban affects hemostatic parameters. Results of a multicenter multiplatform study
- Auto-validation of complete blood counts in an outpatient’s regional laboratory
- Performance evaluation of the digital cell imaging analyzer DI-60 integrated into the fully automated Sysmex XN hematology analyzer system
- Circulating keratan sulfate as a marker of metabolic changes of cartilage proteoglycan in juvenile idiopathic arthritis; influence of growth factors as well as proteolytic and prooxidative agents on aggrecan alterations
- Reference Values and Biological Variations
- Biological variation database: structure and criteria used for generation and update
- Cardiovascular Diseases
- The tumor necrosis factor-α –238G/A and IL-6 –572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls
- Diabetes
- Multicentre evaluation of the Premier Hb9210 HbA1c analyser
- Infectious Diseases
- Determination of quality control limits for serological infectious disease testing using historical data
- Corrigendum
- Enrichment and enumeration of circulating tumor cells by efficient depletion of leukocyte fractions
- Letters to the Editors
- Influence of age and gender on red blood cell distribution width
- Effect of exhaustive running exercise on red blood cell distribution width
- Clinically useful samples and reference change value
- Loss of retinol stability in patient samples
- Evaluation of a new thyroglobulin sensitive assay in patients with differentiated thyroid cancer
- Caution in a case of highly discrepant carbohydrate antigen 19-9 values in an apparently healthy patient taking spirulina: a case report
- Influence of vitamin K antagonist treatment on activated partial thromboplastin time
- Evaluation of the diagnostic characteristics of urinary kidney injury molecule 1 (uKIM-1) and uKIM-1/creatinine ratio in the assessment of incipient diabetic kidney disease
Articles in the same Issue
- Frontmatter
- Editorials
- The new and the old of heparin-induced thrombocytopenia
- Biological variation – reliable data is essential
- Biological variation: back to basics
- Review
- Influence of educational, audit and feedback, system based, and incentive and penalty interventions to reduce laboratory test utilization: a systematic review
- Opinion Papers
- Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus?
- Meeting report: present state of molecular genetics in clinical laboratories. Report on the VII European Symposium on Clinical Laboratory and In Vitro Diagnostic Industry in Barcelona
- Genetics and Molecular Diagnostics
- Non-invasive prenatal diagnosis of monogenic disorders: an optimized protocol using MEMO qPCR with miniSTR as internal control
- A novel biosensor-based microarray assay for the visualized detection of CYP2C19 ∗2, ∗3, ∗4 and ∗5 polymorphisms
- General Clinical Chemistry and Laboratory Medicine
- Preanalytical errors: a preliminary approach to the point of view of primary health care givers
- Comparison of Improvacuter™ tubes with BD Vacutainer™ tubes for various hormones in the aspects of stability and influence of gel separators
- Use of quality indicators to compare point-of-care testing errors in a neonatal unit and errors in a STAT central laboratory
- Serological features of antibodies to protamine inducing thrombocytopenia and thrombosis
- Comparison of three different immunoassays in the diagnosis of heparin-induced thrombocytopenia
- How the direct oral anticoagulant apixaban affects hemostatic parameters. Results of a multicenter multiplatform study
- Auto-validation of complete blood counts in an outpatient’s regional laboratory
- Performance evaluation of the digital cell imaging analyzer DI-60 integrated into the fully automated Sysmex XN hematology analyzer system
- Circulating keratan sulfate as a marker of metabolic changes of cartilage proteoglycan in juvenile idiopathic arthritis; influence of growth factors as well as proteolytic and prooxidative agents on aggrecan alterations
- Reference Values and Biological Variations
- Biological variation database: structure and criteria used for generation and update
- Cardiovascular Diseases
- The tumor necrosis factor-α –238G/A and IL-6 –572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls
- Diabetes
- Multicentre evaluation of the Premier Hb9210 HbA1c analyser
- Infectious Diseases
- Determination of quality control limits for serological infectious disease testing using historical data
- Corrigendum
- Enrichment and enumeration of circulating tumor cells by efficient depletion of leukocyte fractions
- Letters to the Editors
- Influence of age and gender on red blood cell distribution width
- Effect of exhaustive running exercise on red blood cell distribution width
- Clinically useful samples and reference change value
- Loss of retinol stability in patient samples
- Evaluation of a new thyroglobulin sensitive assay in patients with differentiated thyroid cancer
- Caution in a case of highly discrepant carbohydrate antigen 19-9 values in an apparently healthy patient taking spirulina: a case report
- Influence of vitamin K antagonist treatment on activated partial thromboplastin time
- Evaluation of the diagnostic characteristics of urinary kidney injury molecule 1 (uKIM-1) and uKIM-1/creatinine ratio in the assessment of incipient diabetic kidney disease