Comparative analysis of oxidative stress biomarkers (SOD, MDA, and NRF2) in osteoarthritic and non-osteoarthritic human knee articular cartilage

Bintang Soetjahjo; Hendra Cahya; Mujaddid Idulhaq; Asep Santoso; Denny Adriansyah; David Hermawan

Authors

Bintang Soetjahjo Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia and Dr. Moewardi General Province Hospital, Surakarta, Indonesia
Hendra Cahya Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia and Prof Dr. R. Soeharso Orthopedic Hospital, Sukoharjo, Indonesia
Mujaddid Idulhaq Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia and Prof Dr. R. Soeharso Orthopedic Hospital, Sukoharjo, Indonesia
Asep Santoso Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia and Prof Dr. R. Soeharso Orthopedic Hospital, Sukoharjo, Indonesia
Denny Adriansyah Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia and Dr. Moewardi General Province Hospital, Surakarta, Indonesia
David Hermawan Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia and Resident of Orthopedic and Traumatology, Moewardi General Hospital, Surakarta, Indonesia

Keywords:

Articular cartilage, malondialdehyde, NRF2, osteoarthritis, superoxide dismutase

Abstract

Background: Oxidative stress is a key contributor to cartilage degeneration in osteoarthritis; however, direct evidence from human articular cartilage remains limited. Understanding redox imbalance in native human tissue is essential to advance translational strategies for cartilage preservation.

Objectives: This study compared the levels of superoxide dismutase (SOD), malondialdehyde (MDA), and nuclear factor erythroid 2-related factor 2 (NRF2) between osteoarthritic and healthy human knee articular cartilage to determine oxidative stress-related alterations at the tissue level.

Methods: This observational case–control study analyzed knee articular cartilage from patients with endstage osteoarthritis undergoing total knee arthroplasty and non-osteoarthritic controls undergoing anterior cruciate ligament reconstruction. The levels of SOD, MDA, and NRF2 were quantified using an enzymelinked immunosorbent assay, with results expressed as mean ± standard deviation and 95% confidence intervals.

Results: Osteoarthritic cartilage showed significantly reduced SOD levels compared with healthy controls (11.0 ± 2.6 vs. 33.9 ± 12.9 ng/mg protein; P < 0.001), along with markedly elevated MDA concentrations (66.7 ± 18.6 vs. 11.2 ± 3.2 nmol/mg protein; P < 0.001), thus reflecting increased lipid peroxidation. Moreover, NRF2 expression was significantly elevated in the osteoarthritic group (399.6 ± 105.1 vs. 123.8 ± 10.7 ng/mg protein; P < 0.001). All between-group differences were significant with large effect sizes, indicating biologically meaningful separation between groups.

Conclusion: Human osteoarthritic knee cartilage exhibits profound redox imbalance that is characterized by antioxidant failure, increased lipid peroxidation, and insufficient compensatory NRF2 activation. These findings provide direct human tissue-based evidence that supports oxidative stress as a central pathological mechanism in osteoarthritis.

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References

1. Kloppenburg M, Berenbaum F. Osteoarthritis year in review 2019: epidemiology and therapy. Osteoarthritis Cartilage 2020;28:242-8.

https://doi.org/10.1016/j.joca.2020.01.002

2. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet 2019;3931745-59.

https://doi.org/10.1016/S0140-6736(19)30417-9

3. Henrotin Y, Kurz B, Aigner T. Oxygen and reactive oxygen species in cartilage degradation: friends or foes? Osteoarthritis Cartilage 2005;13:643-54.

https://doi.org/10.1016/j.joca.2005.04.002

4. Bolduc JA, Collins JA, Loeser RF. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic Biol Med 2019;132:73-82.

https://doi.org/10.1016/j.freeradbiomed.2018.08.038

5. Scott JL, Gabrielides C, Davidson RK, Swingler TE, Clark IM, Wallis GA, et al. Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Ann Rheum Dis 2010;69:1502-10.

https://doi.org/10.1136/ard.2009.119966

6. Gavriilidis C, Miwa S, von Zglinicki T, Taylor RW, Young DA. Mitochondrial dysfunction in osteoarthritis is associated with down-regulation of superoxide dismutase 2. Arthritis Rheum 2013;65:378-87.

https://doi.org/10.1002/art.37782

7. Saha S, Buttari B, Panieri E, Profumo E, Saso L. An overview of Nrf2 signaling pathway and its role in inflammation. Molecules 2020;25:5474.

https://doi.org/10.3390/molecules25225474

8. Saha S, Rebouh NY. Anti-osteoarthritis mechanism of the Nrf2 signaling pathway. Biomedicines 2023;11:3176.

https://doi.org/10.3390/biomedicines11123176

9. Cai D, Yin S, Yang J, Jiang Q, Cao W. Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis. Arthritis Res Ther 2015;17:269.

https://doi.org/10.1186/s13075-015-0774-3

10. Ma Z, Lu H, Feng X, Du T, Li J, Zhang Q, et al. Nrf2 protects against cartilage endplate degeneration through inhibiting NCOA4-mediated ferritinophagy. Int J Mol Med 2024;53:15.

https://doi.org/10.3892/ijmm.2023.5339

11. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol 2011;23:471-8.

https://doi.org/10.1097/BOR.0b013e328349c2b1

12. Mobasheri A, Batt M. An update on the pathophysiology of osteoarthritis. Ann Phys Rehabil Med 2016;59:333-9.

https://doi.org/10.1016/j.rehab.2016.07.004

13. Engvall E, Perlmann P. Enzyme-linked immunosorbent assay (ELISA): quantitative assay of immunoglobulin G. Immunochemistry 1971;8:871-4.

https://doi.org/10.1016/0019-2791(71)90454-X

14. Mahmood T, Yang PC. Western blot: technique, theory, and trouble shooting. N Am J Med Sci 2012;4:429-34.

https://doi.org/10.4103/1947-2714.100998

15. Regan E, Flannelly J, Bowler R, Tran K, Nicks M, Carbone BD, et al. Extracellular superoxide dismutase and oxidant damage in osteoarthritis. Arthritis Rheum 2005;52:3479-91.

https://doi.org/10.1002/art.21387

16. López-Armada MJ, Fernández-Rodríguez JA, Blanco FJ. Mitochondrial dysfunction and oxidative stress in rheumatoid arthritis. Antioxidants (Basel) 2022;11:1151.

https://doi.org/10.3390/antiox11061151

17. Zahan OM, Serban O, Gherman C, Fodor D. The evaluation of oxidative stress in osteoarthritis. Med Pharm Rep 2020;93:12-22.

https://doi.org/10.15386/mpr-1422

18. Merino de Paz N, Quevedo-Abeledo JC, Gómez-Bernal F, de Vera-González A, Abreu-González P, Martín-González C, et al. Malondialdehyde serum levels in a fully characterized series of 430 rheumatoid arthritis patients. J Clin Med 2024;13:901.

https://doi.org/10.3390/jcm13030901

19. Zhang X, Hou L, Guo Z, Wang G, Xu J, Zheng Z, et al. Lipid peroxidation in osteoarthritis: focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis. Cell Death Discov 2023;9:320.

https://doi.org/10.1038/s41420-023-01613-9

20. Tiku ML, Allison GT, Naik K, Karry SK. Malondialdehyde oxidation of cartilage collagen by chondrocytes. Osteoarthritis Cartilage 2003;11:159-66.

https://doi.org/10.1016/S1063-4584(02)00348-5

21. Lin L, Wu Q, Lu F, Lei J, Zhou Y, Liu Y, et al. Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers. Front Oncol 2023;13:1184079.

https://doi.org/10.3389/fonc.2023.1184079

22. Del Carlo M Jr, Loeser RF. Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels. Arthritis Rheum 2003;48:3419-30.

https://doi.org/10.1002/art.11338

23. Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 2019;27:1578-89.

https://doi.org/10.1016/j.joca.2019.06.011

24. Peshkova M, Lychagin A, Lipina M, Di Matteo B, Anzillotti G, Ronzoni F, et al. Gender-related aspects in osteoarthritis development and progression: a review. Int J Mol Sci 2022;23:2767.

https://doi.org/10.3390/ijms23052767