Interleukin-6 as a Marker of Joint Damage in Osteoarthritis: A Study of Its Pro-inflammatory Impacts

Abstract

Background:

Osteoarthritis (OA) is a degenerative joint disease characterized by a complex pathophysiology involving inflammatory biomarkers.

Objectives:

The current study aimed to investigate the correlation between interleukin-6 (IL-6) serum levels and joint space narrowing (JSN) in patients with knee OA.

Design:

A total of 46 patients clinically diagnosed with knee OA were included in this study.

Methods:

Joint space narrowing was measured using radiographic examinations, whereas blood serum levels of IL-6 were quantified using enzyme-linked immunosorbent assay. Statistical analysis was performed to determine the relationship between IL-6 and JSN.

Results:

The average level of IL-6 was 117.61 (67.05) ng/mL, with JSN measurement of 1.76 (1.31) mm. An inverse correlation found between IL-6 levels and the size of the gap joints in patients with knee OA (r = −.298; P = .044).

Conclusion:

An inverse correlation exists between IL-6 levels and joint impairment in knee OA, suggesting that inflammation plays a crucial role in the progression of the disease.

Plain Language Summary

Osteoarthritis is the most common form of arthritis and occurs when the cartilage that cushions the ends of bones in a joint gradually wears away. Inflammation within the joint is now known to accelerate this damage. One substance released during inflammation is a protein called interleukin-6 (IL-6). We aimed to determine whether the level of IL-6 in the blood is associated with the degree of joint space loss in patients with knee osteoarthritis. We recruited 46 men and women who had been diagnosed by their doctor with knee osteoarthritis. Each person had a standard standing x-ray of the affected knee. On these x-rays, we measured the “joint-space width,” the gap between the bones of the thigh and the shin; a narrower gap means more cartilage loss. We also took a small blood sample and measured the level of IL-6. On average, the joint space was about 1.8 mm wide, and the average IL-6 level was 118 ng/mL. When we compared these 2 numbers for each patient, we found that people with higher IL-6 levels tended to have a narrower joint space. In other words, more inflammation was associated with greater cartilage loss. This study suggests that measuring IL-6 in the blood may one day help doctors estimate the rate of progression of knee osteoarthritis. If future research confirms this, IL-6 might become a simple blood test that guides earlier or more targeted treatment to protect the joint.

Introduction

Osteoarthritis (OA) is the most common type of arthritis. According to World Health Organization data, more than 528 million people worldwide develop OA, which has increased by 113% since 1990. The knee is the most common area of OA (more than 365 million), followed by the hip and hands. The frequency of knee OA is equally high in Southeast Asia, with Indonesia showing a considerable increase in prevalence across age, gender, body mass index (BMI), and physical activity. Increasing knee OA cases lead to limited activity, physical consequences, joint inflammation, as well as painful feelings. Hence, it is not uncommon to be dependent on drugs that also have side effects and will eventually degrade the quality of life of patients with OA.^1-3

Interleukin-6 (IL-6) is a pro-inflammatory cytokine generated by Th-1 cells in response to primary secretory inflammation. Increased IL-6 cytokine levels benefit fluid synovium, and serum samples from patients with OA show a relationship between this cytokine and the degenerative processes that occur. Studies have shown that IL-6 can induce the production of enzymes that break down cartilage tissue, leading to joint degradation. In addition, IL-6 is associated with the development of more severe pain complaints in OA through joint innervation and pain signaling pathways. This suggests that IL-6 is the most critical factor in triggering uncontrolled inflammatory responses.^4-6 Despite increasing evidence supporting IL-6 as a key inflammatory mediator in OA, most existing data originate from Western populations or East Asian cohorts. There is a notable scarcity of data from Southeast Asian populations, including Indonesia, which represents a genetically, environmentally, and metabolically distinct population. Differences in body composition, physical activity patterns, dietary habits, and chronic low-grade inflammation may influence cytokine profiles and disease expression in OA. Consequently, extrapolating IL-6-OA associations from non-Indonesian populations may not fully capture disease characteristics in this setting.

Radiographic assessment of Kellgren-Lawrence and gap joints can be used to diagnose damaged joints in OA. Joint space narrowing (JSN) is a joint examination, which is a major sign of OA and a marker of disease progression. Studies have indicated that JSN occurs in early OA, as well as a considerable increase in pro-inflammatory mediator levels such as IL-1 and TNF-alpha, which is higher in advanced OA.^7,8 However, there is a limited understanding of how inflammation biomarkers, such as IL-6, correspond with the severity of joint injury. Therefore, this study aimed to characterize the relationship between serum IL-6 levels and radiographic JSN in patients with knee OA from an Indonesian population, providing population-specific data in a setting where such evidence remains limited.

Methods

Study participants

A total of 46 patients with knee OA were enrolled in the study. All participants were recruited from a tertiary referral hospital in West Sumatra, Indonesia, representing a predominantly Southeast Asian population. This cohort reflects local demographic characteristics, including a high prevalence of overweight status and advanced age, which are known risk modifiers of OA and systemic inflammation. The inclusion criteria include patients aged 40 years or older with clinically and radiographically confirmed knee OA, as defined by the American College of Rheumatology (ACR) 1997 criteria. Exclusion criteria included inflammatory arthritis, secondary OA due to trauma or infection, history of knee surgery, intra-articular injections or systemic corticosteroid use within the previous 6 months, chronic opioid use, and the presence of systemic inflammatory, autoimmune, or metabolic diseases that could influence serum IL-6 levels. Knee radiographs were assessed using the Kellgren and Lawrence grading system. The study protocol, adhering to the 2000 revised version of the Helsinki Declaration, was approved by the ethics committee of M. Djamil Hospital/Medical Faculty of Andalas University (ID: LB.02.02/5.7/516/2021). This study was designed and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. ⁹

IL-6 cytokine serum

Blood samples (3 mL) were collected from each participant, and the serum was separated by centrifugation at 5000 rpm for 10 minutes. The serum samples were stored at −80°C until all samples had been collected. Interleukin-6 levels were measured using the Human IL-6 ELISA Kit (Bioassay Technology Laboratory, Korain Biotech Co., Ltd., Shanghai, China).

Severity of joint damage

Joint damage was assessed by measuring JSN on knee x-rays. A radiographer measured the joint space closure between the knee bones in millimeters. Joint space narrowing occurs as cartilage degradation progresses, causing a narrowing of the space between bones, typically ranging from 4 to 5 mm in healthy individuals. The severity of knee OA was directly related to the degree of narrowing, with a smaller gap indicating more severe OA. The radiographic assessment was performed by a single radiographer who was blinded to the participants’ clinical data, to minimize potential bias. Each radiograph was measured twice at separate time points by a single experienced radiographer, and the average value was used for statistical analysis. Joint space width was measured manually on standard weight-bearing knee radiographs using a millimeter ruler by a single experienced radiographer.

Data analysis

Demographic data, including age, gender, and BMI, were obtained from study participants and included in the study’s baseline characteristics. Levels of IL-6 cytokines and joint gap measurements were also computed, and the means of each variable were correlated using bivariate analysis with Spearman correlation coefficient (nonparametric) test in SPSS for Windows. Statistical significance was considered when P < .05.

Results

Baseline characteristics of patients with knee OA

Table 1 shows the baseline characteristics of research participants. Males represented a smaller proportion of the study population compared with females, with 37% of participants being male and 63% female. Regarding BMI, most participants were classified as overweight, followed by those with a normal weight, and then underweight individuals. Average JSN measurement in this study was 1.76 (1.31) mm, and the average IL-6 serum was 117.61 (67.05) pg/mL.

Table 1.

Baseline characteristics of study participants.

Characteristics	No. (%)	Mean (SD)
Age		66.11 (10.44)
Gender
• Male	17 (37)
• Female	29 (63)
BMI, kg/m2
• <18.5	3 (6.5)
• 18.5-22.9	18 (39.1)
• >23	25 (54.3)
Kellgren-Lawrence (KL)
• Mild (1-2)	23 (50)
• Moderate-severe (3-4)	23 (50)
Joint space narrowing, mm		1.76 (1.31)
Serum IL-6, pg/mL		117.61 (67.05)

Correlation analysis between IL-6 serum and JSN of patients with knee OA

As the primary outcome of this study, we investigated the relationship between serum IL-6 and JSN measurement. Figure 1 illustrates a significant inverse correlation between the 2 variables, with a correlation coefficient of r = −.298 and a P value of .044. This suggests that higher IL-6 levels are associated with more severe JSN in the patients with knee OA.

Figure 1.

Correlation between IL-6 serum and joint space narrowing of patients with knee OA.

Discussion

Beyond confirming an inverse association between serum IL-6 levels and JSN, the present study provides population-specific evidence from an Indonesian cohort, addressing a critical gap in OA biomarker research in Southeast Asia. The key finding of this study is the inverse relationship between pro-inflammatory cytokines, IL-6 serum levels, and JSN measurements in patients with knee OA. This result supports previous research, suggesting that elevated IL-6 levels are associated with more severe joint damage in OA. However, there is no direct association between the onset of joint cartilage damage in OA and radiological imaging, which complicates the detection of early OA progression and the prediction of more severe tissue damage. Joint space narrowing in OA implies loss of joint cartilage in the genu, where research suggests that radiological manifestations usually arise after 10 to 20 years of damage to the meniscus or anterior cruciate ligament, and the appearance of JSN is also a marker of pre-existing OA have reached an advanced stage.^10,11

This study found that patients with genu OA had higher serum IL-6 levels. At the beginning of inflammation, anabolic and catabolic processes occur, characterized by an increase in several pro-inflammatory cytokines. Interleukin-6 is hypothesized to play a role in OA via the classical pathway, activating excessive JAK/STAT3 due to the ongoing inflammatory response in OA and influencing the severity of OA. The results of this study indicate that high levels of IL-6, and the inverse correlation with JSN, suggest that an increase in pro-inflammatory cytokines might be subsequently associated with the severity of OA.^12,13

The limited availability of OA biomarker data from Indonesian populations underscores the relevance of these findings. Genetic background, lifestyle, and environmental exposures differ substantially from Western and East Asian populations, potentially influencing cytokine expression and inflammatory pathways. In Indonesia, higher rates of overweight status, physically demanding occupations, and delayed health care access may further modulate IL-6 levels and disease severity.^4,5 Our findings suggest that IL-6 may serve as a relevant inflammatory marker in this specific population context.

According to research, concerns of pain in patients with OA genu do not always result in damage in the radiological picture of OA genu, so the intervention of OA genu frequently comes with a severe condition, even requiring surgery such as total knee replacement because it is only detected after an advanced stage.^11,12 The limitation of this study is that this study excluded genetic factors, family history, nutritional influences, physical activity, and the duration of the patient’s OA, all of which may impact the correlation with IL-6 levels. In addition, the lack of comparative IL-6 reference data from healthy Indonesian controls limits population-level interpretation. A prior power analysis for sample size calculation was not performed in this study, which may limit the statistical power of the study and increase the risk of a type II error. However, this study provides an essential baseline for future population-based and longitudinal research in Indonesian and Southeast Asian OA cohorts. In addition, the assessment of IL-6 as an inflammatory marker is conducted through serum analysis, rather than by investigating synovial fluid or synovial tissue, which are more specific for evaluating joint inflammations. Based on the findings of this study, it is expected that establishing a connection between IL-6 cytokine levels and JSN will enable the identification of OA earlier, management of disease progression, and the development of a biomarker for monitoring the clinical effectiveness of treatment in patients with OA.

Limitations

Several limitations to this study should be addressed. First, this study employed a cross-sectional design, which limits the ability to draw causal conclusions between serum IL-6 levels and JSN. Second, no a priori power analysis was undertaken for sample size calculation, thereby limiting the statistical power of the findings and increasing the likelihood of a type II error. A single radiographer assessed third, JSN, and while blinding was used to reduce bias, no repeated measures or formal assessments of intra-observer reliability were undertaken. Fourth, serum samples were used to measure IL-6 levels, rather than synovial fluid or synovial tissue, which may provide a more direct reflection of joint inflammation. Furthermore, potential confounding variables, such as disease duration, physical activity level, occupational load, genetic background, and dietary condition, were not considered. Finally, the small sample size and single-center design may limit the applicability of our findings. Despite these limitations, this work contributes useful preliminary, population-specific data from an Indonesian cohort, where knowledge on inflammatory biomarkers in OA is limited.

Conclusion

This study demonstrates a significant inverse association between serum IL-6 levels and radiographic JSN in patients with knee OA. These findings suggest that higher systemic inflammatory activity is associated with greater structural joint damage. Importantly, this study provides preliminary population-specific evidence from an Indonesian cohort, where data on inflammatory biomarkers in OA remain limited. While the cross-sectional design and sample size warrant cautious interpretation, the results support the potential role of IL-6 as a biomarker of disease severity, highlighting the need for larger, longitudinal studies to confirm its clinical utility in diverse populations.