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Correlation of inflammatory mediators with osteophyte formation in end-stage knee osteoarthritis
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  • Published: 27 January 2026

Correlation of inflammatory mediators with osteophyte formation in end-stage knee osteoarthritis

  • Doo-Ho Kim1 na1,
  • Yoon-Seok Youm2 na1,
  • Sung-Do Cho3,
  • Sang-Heon Oh4,
  • Su Jin Choi1 &
  • …
  • Ki-Bong Park4 

Scientific Reports , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Biomarkers
  • Diseases
  • Medical research

Abstract

Osteoarthritis (OA) is a prevalent degenerative joint disorder with varying clinical and radiological presentations. This study aimed to investigate the relationship between pro-inflammatory mediators in serum and synovial fluid (SF) and osteophyte size in patients with end-stage knee OA. Forty-four patients (58 knees) who underwent total knee arthroplasty were included. Serum and SF levels of matrix metalloproteinase-1 (MMP-1), interleukin-8 (IL-8), and interleukin-18 (IL-18) were measured using enzyme-linked immunosorbent assay. Radiographic parameters, including osteophyte size, were assessed using on standing anteroposterior knee X-rays. Pearson’s and partial correlation analyses were used to evaluate associations. A positive correlation was found between serum and SF IL-18 levels (r = 0.64, P < 0.001) and between SF MMP-1 and IL-8 levels (r = 0.28, P = 0.03). A significant positive correlation was found between patient age and femur osteophyte size (r = 0.32, P = 0.02). SF IL-18 levels positively correlated with both femur (r = 0.36, P = 0.005) and tibia (r = 0.28, P = 0.04) osteophyte sizes. The partial correlation between SF IL-18 and femur osteophyte size remained significant after adjusting for age (r = 0.3, P = 0.02) and body mass index (r = 0.38, P = 0.003). Elevated SF IL-18 levels were associated with increased osteophyte size in patients with end-stage knee OA, suggesting a potential role for IL-18 in osteophyte formation. Elevated SF IL-18 levels may reflect underlying inflammatory activity in OA and could serve as a potential biomarker or therapeutic target in advanced disease.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. And anonymized raw data are attached as supplementary files.

Abbreviations

MMP:

Matrix metalloproteinage

IL:

Interleukin

SF:

Synovial fluid

OA:

Osteoarthritis

TKA:

Total knee arthroplasty

K-L:

Kellgren-Lawrence

IRB:

Institutional Review Board

ELISA:

Enzyme-linked immunosorbent assay

BMI:

Body mass index

PACS:

Picture Archiving and Communication System

IBM:

International Business Machine

FOST:

Femoral osteophyte area

TOST:

Tibial osteophyte area

References

  1. Kinds, M. B. et al. Identifying phenotypes of knee osteoarthritis by separate quantitative radiographic features may improve patient selection for more targeted treatment. J. Rheumatol. 40, 891–902. https://doi.org/10.3899/jrheum.121004 (2013).

    Google Scholar 

  2. Berenbaum, B. J. W. & Lafeber, F. Osteoarthritis: An update with relevance for clinical practice. Lancet 377, 2115–2126. https://doi.org/10.1016/S0140-6736(11)60234-2 (2011).

    Google Scholar 

  3. Duryea, J. et al. Comparison of radiographic joint space width with magnetic resonance imaging cartilage morphometry: Analysis of longitudinal data from the osteoarthritis initiative. Arthritis Care Res. 62, 932–937. https://doi.org/10.1002/acr.20148 (2010).

    Google Scholar 

  4. Kerkhof, H. J. et al. Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: The TREATOA consortium. Osteoarthr. Cartil. 19, 254–264. https://doi.org/10.1016/j.joca.2010.10.027 (2011).

    Google Scholar 

  5. Demirağ., M. D. et al. Associations between obesity and the radiographic phenotype in knee osteoarthritis. Turk. J. Med. Sci. 47, 424–429. https://doi.org/10.3906/sag-1512-26 (2017).

    Google Scholar 

  6. Tonge, D. P., Pearson, M. J. & Jones, S. W. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics. Osteoarthr. Cartil. 22, 609–621. https://doi.org/10.1016/j.joca.2014.03.004 (2014).

    Google Scholar 

  7. Mukherjee, A. & Das, B. The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis. Biomater. Biosyst. 13, 100090. https://doi.org/10.1016/j.bbiosy.2024.100090 (2024).

    Google Scholar 

  8. Mehana, E. E., Khafaga, A. F. & El-Blehi, S. S. The role of matrix metalloproteinases in osteoarthritis pathogenesis: An updated review. Life Sci. 234, 116786. https://doi.org/10.1016/j.lfs.2019.116786 (2019).

    Google Scholar 

  9. Heard, B. J. et al. Matrix metalloproteinase protein expression profiles cannot distinguish between normal and early Osteoarthritic synovial fluid. BMC Musculoskelet. Disord. 13, 126. https://doi.org/10.1186/1471-2474-13-126 (2012).

    Google Scholar 

  10. Favero, M. et al. Inflammatory molecules produced by meniscus and synovium in early and end-stage osteoarthritis: A coculture study. J. Cell. Physiol. 234, 11176–11187. https://doi.org/10.1002/jcp.27766 (2019).

    Google Scholar 

  11. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635. https://doi.org/10.1038/nrrheum.2010.159 (2010).

    Google Scholar 

  12. Koh, S. M. et al. Elevated plasma and synovial fluid interleukin-8 and interleukin-18 May be associated with the pathogenesis of knee osteoarthritis. Knee 27, 26–35. https://doi.org/10.1016/j.knee.2019.10.028 (2020).

    Google Scholar 

  13. Hwang, I. Y. et al. Synovial fluid levels of TWEAK and matrix metalloproteinase 1 in patients with osteoarthritis, and associations with disease severity. J. Orthop. Surg. 26, 2309499018760112. https://doi.org/10.1177/2309499018760112 (2018).

    Google Scholar 

  14. Monibi, F. et al. Identification of synovial fluid biomarkers for knee osteoarthritis and correlation with radiographic assessment. J. Knee Surg. 29, 242–247. https://doi.org/10.1055/s-0035-1549022 (2016).

    Google Scholar 

  15. Wang, Y. et al. Correlation between plasma, synovial fluid and articular cartilage Interleukin-18 with radiographic severity in 33 patients with osteoarthritis of the knee. Clin. Exp. Med. 14, 297–304. https://doi.org/10.1007/s10238-013-0251-8 (2014).

    Google Scholar 

  16. Waszczykowski, M., Fabiś-Strobin, A., Bednarski, I., Narbutt, J. & Fabiś, J. Serum and synovial fluid concentrations of interleukin-18 and interleukin-20 in patients with osteoarthritis of the knee and their correlation with other markers of inflammation and turnover of joint cartilage. Arch. Med. Sci. 18, 448–458. https://doi.org/10.5114/aoms.2020.96717 (2020).

    Google Scholar 

  17. Junker, S. et al. Expression of adipokines in osteoarthritis osteophytes and their effect on osteoblasts. Matrix Biol. 62, 75–91. https://doi.org/10.1016/j.matbio.2016.11.005 (2017).

    Google Scholar 

  18. Hossain, F. M., Hong, Y., Jin, Y., Choi, J. & Hong, Y. Physiological and pathological role of circadian hormones in osteoarthritis: Dose-dependent or time-dependent? J. Clin. Med. 8, 1415. https://doi.org/10.3390/jcm8091415 (2019).

    Google Scholar 

  19. Yin, X. et al. Research progress on macrophage polarization during osteoarthritis disease progression: A review. J. Orthop. Surg. Res. 19, 584. https://doi.org/10.1186/s13018-024-05052-9 (2024).

    Google Scholar 

  20. Chong, T. K. Y., Tan, J. R., Ma, C. A., Wong, S. B. S. & Leung, Y. Y. Association of adipokines with severity of knee osteoarthritis assessed clinically and on magnetic resonance imaging. Osteoarthr. Cartil. Open 5, 100405. https://doi.org/10.1016/j.ocarto.2023.100405 (2023).

    Google Scholar 

  21. Sakao, K. et al. Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in osteoarthritis. J. Bone Min. Metab. 27, 412–423. https://doi.org/10.1007/s00774-009-0058-6 (2009).

    Google Scholar 

  22. Dell’Isola, A. & Steultjens, M. Classification of patients with knee osteoarthritis in clinical phenotypes: Data from the osteoarthritis initiative. PLoS One 13, e0191045. https://doi.org/10.1371/journal.pone.0191045 (2018).

    Google Scholar 

  23. Schmitt, J. et al. Indication criteria for total knee arthroplasty in patients with lritis - A multi-perspective consensus study. Z. Orthop. Unfall 155, 539–548. https://doi.org/10.1055/s-0043-115120 (2017).

    Google Scholar 

  24. Syggelos, S. A. et al. In vitro effects of non-steroidal anti-inflammatory drugs on cytokine, prostanoid and matrix metalloproteinase production by interface membranes from loose hip or knee endoprostheses. Osteoarthr. Cartil. 15, 531–542. https://doi.org/10.1016/j.joca.2006.11.003 (2007).

    Google Scholar 

  25. Olson, C. P. et al. Effect of anti-inflammatory treatments on patient outcomes and concentrations of inflammatory modulators in the post-surgical and post-traumatic tibiofemoral joint setting: A narrative review. Ann. Jt. 9, 9. https://doi.org/10.21037/aoj-23-55 (2024).

    Google Scholar 

  26. Hendrix, J. M. & Garmon, E. H. American Society of Anesthesiologists physical status classification system. In StatPearls (StatPearls Publishing, 2025).

  27. Bioanalytical method validation guidance for industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf.

  28. Nagaosa, Y., Lanyon, P. & Doherty, M. Characterisation of size and direction of osteophyte in knee osteoarthritis: a radiographic study. Ann. Rheum. Dis. 61, 319–324. https://doi.org/10.1136/ard.61.4.319 (2002).

    Google Scholar 

  29. Oka, H. et al. Fully automatic quantification of knee osteoarthritis severity on plain radiographs. Osteoarthr. Cartil. 16, 1300–1306. https://doi.org/10.1016/j.joca.2008.03.011 (2008).

    Google Scholar 

  30. Okumura, N. et al. Effects of malalignment and disease activity on osteophyte formation in knees of rheumatoid arthritis patients. J. Orthop. Surg. 28, 2309499020911852. https://doi.org/10.1177/2309499020911852 (2020).

    Google Scholar 

  31. Neogi, T. et al. Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ 7339, b2844. https://doi.org/10.1136/bmj.b2844 (2009).

    Google Scholar 

  32. Pottenger, L. A., Phillips, F. M. & Draganich, L. F. The effect of marginal osteophytes on reduction of varus-valgus instability in osteoarthritic knees. Arthritis Rheum. 33, 853–858. https://doi.org/10.1002/art.1780330612 (1990).

    Google Scholar 

  33. van der Kraan, P. M. & van den Berg, W. B. Osteophytes: relevance and biology. Osteoarthr. Cartil. 15, 237–244. https://doi.org/10.1016/j.joca.2006.11.006 (2007).

    Google Scholar 

  34. Ruan, G. et al. Associations between knee structural measures, circulating inflammatory factors and MMP13 in patients with knee osteoarthritis. Osteoarthr. Cartil. 26, 1063–1069. https://doi.org/10.1016/j.joca.2018.05.003 (2018).

    Google Scholar 

  35. Marijnissen, A. C. et al. Knee images digital analysis (KIDA): A novel method to quantify individual radiographic features of knee osteoarthritis in detail. Osteoarthr. Cartil. 16, 234–243. https://doi.org/10.1016/j.joca.2007.06.009 (2008).

    Google Scholar 

  36. Hunter, D. J. et al. Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI osteoarthritis knee score). Osteoarthr. Cartil. 19, 990–1002. https://doi.org/10.1016/j.joca.2011.05.004 (2011).

    Google Scholar 

  37. Pierzchala, A. W., Kusz, D. J. & Hajduk, G. CXCL8 and CCL5 expression in synovial fluid and blood serum in patients with osteoarthritis of the knee. Arch. Immunol. Ther. Exp. 59, 151–155. https://doi.org/10.1007/s00005-011-0115-4 (2011).

    Google Scholar 

  38. Shen, J., Li, S. & Chen, D. TGF-β signaling and the development of osteoarthritis. Bone Res. 2, 14002. https://doi.org/10.1038/boneres.2014.2 (2014).

    Google Scholar 

  39. van der Kraan, P. M., Goumans, M. J., Davidson, B. & ten Dijke, E. Age-dependent alteration of TGF-β signalling in osteoarthritis. Cell. Tissue Res. 347, 257–265. https://doi.org/10.1007/s00441-011-1194-6 (2012).

    Google Scholar 

  40. Zhang, R. K. et al. Mechanical stress contributes to osteoarthritis development through the activation of transforming growth factor beta 1 (TGF-β1). Bone Jt. Res. 7, 587–594. https://doi.org/10.1302/2046-3758.711.BJR-2018-0057.R1 (2018).

    Google Scholar 

  41. Yoshino, M. Roles of specific cytokines in bone remodeling and hematopoiesis in gaucher disease. Pediatr. Int. 49, 959–965. https://doi.org/10.1111/j.1442-200X.2007.02502.x (2007).

    Google Scholar 

  42. Knapik, M., Żelazo, D. A., Osowiecka, K. & Krajewska-Włodarczyk, M. Efficacy of Anti-Interleukin-1 therapeutics in the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials from the years 2000 to 2023. J. Clin. Med. 13, 2859. https://doi.org/10.3390/jcm13102859 (2024).

    Google Scholar 

  43. Yoshino, M. et al. Roles of specific cytokines in bone remodeling and hematopoiesis in Gaucher disease. Pediatr. Int. 49, 959–965. https://doi.org/10.1111/j.1442-200X.2007.02502.x (2007).

  44. Asai, S. et al. Periarticular osteophyte formation protects against total knee arthroplasty in rheumatoid arthritis patients with advanced joint damage. Clin. Rheumatol. 39, 3331–3339. https://doi.org/10.1007/s10067-020-05140-1 (2020).

    Google Scholar 

  45. Waldstein, W., Kasparek, M. F., Faschingbauer, M., Windhager, R. & Boettner, F. Lateral-compartment osteophytes are not associated with lateral-compartment cartilage degeneration in arthritic varus knees. Clin. Orthop. Relat. Res. 475, 1386–1392. https://doi.org/10.1007/s11999-016-5155-y (2017).

    Google Scholar 

  46. Calich, A. L., Domiciano, D. S. & Fuller, R. Osteoarthritis: Can anti-cytokine therapy play a role in treatment? Clin. Rheumatol. 29, 451–455. https://doi.org/10.1007/s10067-009-1352-3 (2010).

    Google Scholar 

  47. Malemud, C. J. Anticytokine therapy for osteoarthritis: evidence to date. Drugs Aging 27, 95–115. https://doi.org/10.2165/11319950-000000000-00000 (2010).

    Google Scholar 

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Author information

Author notes
  1. Doo-Ho Lim and Yoon-Seok Youm contributed equally to this work and are co-first authors.

Authors and Affiliations

  1. Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea

    Doo-Ho Kim & Su Jin Choi

  2. Department of Orthopedic Surgery, Samsan Hospital, Gangwon-do, Republic of Korea

    Yoon-Seok Youm

  3. Department of Orthopedic Surgery, Dongcheondongkang Hospital, Ulsan, Republic of Korea

    Sung-Do Cho

  4. Department of Orthopedic Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea

    Sang-Heon Oh & Ki-Bong Park

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Contributions

DH Lee: conceptualization, software, validation, writing—review and editingYS Yeom: conceptualization, methodology, validation, writing—original draft preparationSD Cho: validation, formal analysis, writing—review and editingSH Oh: formal analysis, data curation, writing—original draft preparationSJ Choi: methodology, formal analysis, data curation, supervision, writing—review and editingKB Park: conceptualization, methodology, formal analysis, data curation, writing—original draft preparation, writing—review and editingAll authors have read and agreed to the publication of the finale version of the manuscript.

Corresponding author

Correspondence to Ki-Bong Park.

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The authors declare no competing interests.

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The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Ulsan University Hospital (protocol code UUH-2014-6). Informed Consent Statement: Informed consent was obtained from all participants involved in the study. Written informed consent to publish this paper was also obtained from the patients.

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Written informed consent was obtained from each patient.

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Kim, DH., Youm, YS., Cho, SD. et al. Correlation of inflammatory mediators with osteophyte formation in end-stage knee osteoarthritis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37394-1

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  • Received: 31 May 2025

  • Accepted: 21 January 2026

  • Published: 27 January 2026

  • DOI: https://doi.org/10.1038/s41598-026-37394-1

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Keywords

  • Osteoarthritis
  • Osteophytes
  • Serum
  • Synovial fluid
  • Matrix metalloproteinases
  • Interleukin
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