Serum CS/DS, IGF-1, and IGFBP-3 As Biomarkers of Cartilage Remodeling in Juvenile Idiopathic Arthritis: Diagnostic and Therapeutic Implications

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2025 Jan 8

PMID 39766233

Authors

Katarzyna Winsz-Szczotka

Kornelia Kuznik-Trocha

Ewa M Kozma

Boguslaw Zeglen

Anna Gruenpeter

Grzegorz Wisowski

Katarzyna Komosinska-Vassev

Krystyna Olczyk

Affiliations

Soon will be listed here.

Abstract

Cartilage destruction in juvenile idiopathic arthritis (JIA) is diagnosed, often too late, on basis of clinical evaluation and radiographic imaging. This case-control study investigated serum chondroitin/dermatan sulfate (CS/DS) as a potential biochemical marker of cartilage metabolism, aiming to improve early diagnosis and precision treatment for JIA. We also measured the levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) (using ELISA methods) in JIA patients ( = 55) both before and after treatment (prednisone, sulfasalazine, methotrexate, administered together), and analyzed their relationships with CS/DS levels. Untreated JIA patients [8.26 µg/mL (6.25-9.66)], especially untreated girls [8.57 µg/mL (8.13-9.78)] and patients with a polyarticular form of the disease [7.09 µg/mL (5.63-8.41)], had significantly reduced levels of serum CS/DS compared with the control [14.48 µg/mL (10.23-15.77)]. Therapy resulted in a significant increase in this parameter, but without normalization. We also found significantly lower levels of IGF-1 [66.04 ng/mL (49.45-96.80)] and IGFBP-3 [3.37 ng/mL (2.65-4.88)] in untreated patients compared with the control [96.92 ng/mL (76.04-128.59), 4.84 ng/mL (4.21-7.750), respectively]. Based on receiver operating characteristic (ROC) curve analysis, the blood concentration of CS/DS demonstrated the highest diagnostic power (AUC = 0.947) for JIA among all the tested markers. Untreated patients showed significant correlations between CS/DS and IGF-1 (r = -0.579, = 0.0000), IGFBP-3 (r = -0.506, = 0.0001), and C-reactive protein (r = 0.601, = 0.0005). The observed changes in CS/DS during the course of JIA, influenced by both impairment of the IGF/IGFBP axis and inflammation, indicate the need for continued therapy to protect patients from potential disability. We suggest that CS/DS may be a useful biomarker of disease activity and could be employed to assess treatment efficacy and progress toward remission.

References

Wisowski G, Pudelko A, Paul-Samojedny M, Komosinska-Vassev K, Kozma E . Dermatan Sulfate Affects the Activation of the Necroptotic Effector MLKL in Breast Cancer Cell Lines via the NFκB Pathway and Rac-Mediated Oxidative Stress. Biomolecules. 2024; 14(7). PMC: 11274702. DOI: 10.3390/biom14070829. View

Kuznik-Trocha K, Winsz-Szczotka K, Lachor-Motyka I, Dabkowska K, Wojdas M, Olczyk K . The Effects of TNF-α Inhibition on the Metabolism of Cartilage: Relationship between KS, HA, HAPLN1 and ADAMTS4, ADAMTS5, TOS and TGF-β1 Plasma Concentrations in Patients with Juvenile Idiopathic Arthritis. J Clin Med. 2022; 11(7). PMC: 8999578. DOI: 10.3390/jcm11072013. View

Winsz-Szczotka K, Komosinska-Vassev K, Kuznik-Trocha K, Gruenpeter A, Lachor-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(9):829-34. DOI: 10.1016/j.clinbiochem.2014.01.027. View

Peake N, Khawaja K, Myers A, Jones D, Cawston T, Rowan A . Levels of matrix metalloproteinase (MMP)-1 in paired sera and synovial fluids of juvenile idiopathic arthritis patients: relationship to inflammatory activity, MMP-3 and tissue inhibitor of metalloproteinases-1 in a longitudinal study. Rheumatology (Oxford). 2005; 44(11):1383-9. DOI: 10.1093/rheumatology/kei025. View

Vallet S, Clerc O, Ricard-Blum S . Glycosaminoglycan-Protein Interactions: The First Draft of the Glycosaminoglycan Interactome. J Histochem Cytochem. 2020; 69(2):93-104. PMC: 7841700. DOI: 10.1369/0022155420946403. View

Wong S, MacRae V, Gracie J, McInnes I, Galea P, Gardner-Medwin J . Inflammatory cytokines in juvenile idiopathic arthritis: effects on physical growth and the insulin-like-growth factor axis. Growth Horm IGF Res. 2008; 18(5):369-378. DOI: 10.1016/j.ghir.2008.01.006. View

Winsz-Szczotka K, Komosinska-Vassev K, Kuznik-Trocha K, Siwiec A, Zeglen B, Olczyk K . 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. Clin Chem Lab Med. 2014; 53(2):291-7. DOI: 10.1515/cclm-2014-0441. View

Alcaide-Ruggiero L, Cugat R, Dominguez J . Proteoglycans in Articular Cartilage and Their Contribution to Chondral Injury and Repair Mechanisms. Int J Mol Sci. 2023; 24(13). PMC: 10341989. DOI: 10.3390/ijms241310824. View

Tsatsoulis A, Siamopoulou A, Petsoukis C, Challa A, Bairaktari E, Seferiadis K . Study of growth hormone secretion and action in growth-retarded children with juvenile chronic arthritis (JCA). Growth Horm IGF Res. 1999; 9(2):143-9. DOI: 10.1054/ghir.1999.0099. View

10.

Guszczyn T, Rzeczycka J, Popko J . IGF-I and IGF-binding proteins in articular exudates of children with post-traumatic knee damage and juvenile idiopathic arthritis. Pathobiology. 2009; 76(5):260-6. DOI: 10.1159/000228902. View

11.

Petty R, Southwood T, Manners P, Baum J, Glass D, Goldenberg J . International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004; 31(2):390-2. View

12.

Ahmed S, Farquharson C . The effect of GH and IGF1 on linear growth and skeletal development and their modulation by SOCS proteins. J Endocrinol. 2010; 206(3):249-59. DOI: 10.1677/JOE-10-0045. View

13.

Bechtold S, Ripperger P, Dalla Pozza R, Bonfig W, Hafner R, Michels H . Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab. 2007; 92(8):3013-8. DOI: 10.1210/jc.2007-0544. View

14.

BLUMENKRANTZ N, ASBOE-HANSEN G . New method for quantitative determination of uronic acids. Anal Biochem. 1973; 54(2):484-9. DOI: 10.1016/0003-2697(73)90377-1. View

15.

Choukair D, Hugel U, Sander A, Uhlmann L, Tonshoff B . Inhibition of IGF-I-related intracellular signaling pathways by proinflammatory cytokines in growth plate chondrocytes. Pediatr Res. 2014; 76(3):245-51. DOI: 10.1038/pr.2014.84. View

16.

Wojdas M, Dabkowska K, Winsz-Szczotka K . Alterations of Extracellular Matrix Components in the Course of Juvenile Idiopathic Arthritis. Metabolites. 2021; 11(3). PMC: 7996267. DOI: 10.3390/metabo11030132. View

17.

Wen C, Xu L, Xu X, Wang D, Liang Y, Duan L . Insulin-like growth factor-1 in articular cartilage repair for osteoarthritis treatment. Arthritis Res Ther. 2021; 23(1):277. PMC: 8556920. DOI: 10.1186/s13075-021-02662-0. View

18.

Bratulic S, Limeta A, Maccari F, Galeotti F, Volpi N, Levin M . Analysis of normal levels of free glycosaminoglycans in urine and plasma in adults. J Biol Chem. 2022; 298(2):101575. PMC: 8888457. DOI: 10.1016/j.jbc.2022.101575. View

19.

dAngelo D, Di Donato G, Breda L, Chiarelli F . Growth and puberty in children with juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2021; 19(1):28. PMC: 7953722. DOI: 10.1186/s12969-021-00521-5. View

20.

Forbes B, Blyth A, Wit J . Disorders of IGFs and IGF-1R signaling pathways. Mol Cell Endocrinol. 2020; 518:111035. DOI: 10.1016/j.mce.2020.111035. View