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
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Hendrix, J. M. & Garmon, E. H. American Society of Anesthesiologists physical status classification system. In StatPearls (StatPearls Publishing, 2025).
Bioanalytical method validation guidance for industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Malemud, C. J. Anticytokine therapy for osteoarthritis: evidence to date. Drugs Aging 27, 95–115. https://doi.org/10.2165/11319950-000000000-00000 (2010).
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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.
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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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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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DOI: https://doi.org/10.1038/s41598-026-37394-1


