Temporomandibular disorders (TMD) are a group of musculoskeletal and neuromuscular conditions involving the temporomandibular joint (TMJ), masticatory muscles and related structures. Patients may present with pain, joint sounds, restricted mouth opening and difficulty with chewing or speaking. These problems can reduce daily function and quality of life. The Diagnostic Criteria for Temporomandibular Disorders provide a validated system for identifying common pain related muscular and joint conditions (Schiffman et al., 2014). Systematic reviews suggest that TMD affects almost one third of adults although estimates vary with the population and diagnostic method (Valesan et al., 2021; Alqutaibi et al., 2025). The development of TMD is complex. Mechanical overload, muscle overuse, trauma, psychological distress, sleep disturbance and altered pain processing may contribute to its onset or persistence. Repeated loading of the joint and masticatory muscles can reduce local oxygen supply and increase the formation of reactive oxygen species. When these molecules exceed the available antioxidant defence they can damage lipids, proteins and cellular structures. Oxidative stress may also promote inflammatory signalling, pain sensitisation and degradation of the joint matrix. These processes may contribute to pain and reduced mandibular movement (Braz et al., 2020; Lee et al., 2004). Saliva provides a simple and non-invasive biological sample for studying these processes. It can be collected repeatedly without venepuncture and may contain markers of oxidative damage, antioxidant activity, inflammation and tissue breakdown. Malondialdehyde (MDA) is commonly used as a marker of lipid peroxidation while total antioxidant capacity (TAC) reflects the combined activity of salivary antioxidants. Interleukin 1 beta (IL-1β) and interleukin 6 (IL-6) are linked with inflammation and pain. Matrix metalloproteinase 3 (MMP-3) contributes to extracellular matrix turnover and may indicate tissue degradation. However salivary concentrations can also be influenced by oral inflammation, smoking, medication, stress and the method of sample collection (Rodríguez de Sotillo et al., 2011; Kazan et al., 2023). Previous findings are not consistent. Omidpanah and colleagues reported higher salivary malondialdehyde in patients with TMD but found no significant group differences in total antioxidant capacity or catalase activity (Omidpanah et al., 2020). In contrast a study of myogenous TMD found higher antioxidant activity and lower levels of some oxidative markers (Madariaga et al., 2021). Kazan and colleagues found no significant differences in salivary malondialdehyde or interleukin 6 between patients and controls (Kazan et al., 2023). These differences may reflect small samples, different TMD phenotypes and variation in laboratory methods. Other studies support a role for biochemical pathways in TMD. Altered salivary and plasma pain related proteins have been reported in patients with TMD myalgia (Jasim et al., 2020). Salivary matrix metalloproteinase 3 has also been associated with condylar changes in temporomandibular joint osteoarthritis (Shoukri et al., 2019). Reviews conclude that salivary biomarkers may help explain TMD pathophysiology but no single marker has adequate evidence for diagnosis or assessment of severity (Alam et al., 2024; Soares et al., 2025). An important gap remains between biochemical findings and clinical function. A combined assessment may provide a clearer view of biological activity and functional impairment. The research question was whether adults with TMD have different salivary biomarker levels and greater mandibular dysfunction than adults without TMD and whether biomarker levels are associated with functional limitation. The aim was to compare selected salivary biomarkers and mandibular function between adults with TMD and controls without TMD and to examine the relationship between biomarker levels and functional impairment. Objectives 1. To compare salivary levels of malondialdehyde, total antioxidant capacity, interleukin 1 beta, interleukin 6 and matrix metalloproteinase 3 between TMD cases and controls. 2. To compare mandibular movements, pain intensity and Jaw Functional Limitation Scale scores between TMD cases and controls. 3. To assess the independent association between salivary biomarker levels and mandibular dysfunction after adjustment for relevant confounding factors.

This analytical case-control study was conducted at KEMU/ Mayo Hospital, Lahore, Pakistan from 1 March 2024 to 28 February 2026. It compared adults diagnosed with temporomandibular disorders with adults without TMD in a 1:1 ratio. Reporting followed the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. The Ethical Committee of KEMU/ Mayo Hospital, Lahore approved the study. The study followed the Declaration of Helsinki and relevant national guidance. Written informed consent was obtained from every participant before data collection. Participants were assigned study codes and identifying information was stored separately from research data. Results were reported in grouped form. Participants Adults aged 18 to 60 years attending the hospital were screened. Consecutive patients meeting the Diagnostic Criteria for Temporomandibular Disorders were recruited as cases. Cases had pain related TMD for at least three months and were classified as having muscular, joint related or combined TMD. Controls were recruited from the same population and were frequency matched by age and sex. Controls had no current symptoms, previous TMD diagnosis or positive DC/TMD findings. Exclusion criteria were acute dental pain, oral infection, severe periodontal inflammation, recent maxillofacial trauma, major TMJ surgery or a disease affecting inflammation or mandibular movement. Pregnancy, breastfeeding, corticosteroids, immunosuppressive medicines, recent antibiotics, regular antioxidant supplements and current TMD treatment also led to exclusion. Sample size The sample size was calculated for comparison of the main salivary biomarker. A standardised effect size of 0.50, power of 80 percent and significance level of 5 percent required 64 participants per group. After allowing for incomplete data the planned sample was 140 participants with 70 cases and 70 controls. Clinical and functional assessment A trained and calibrated examiner diagnosed TMD using the DC/TMD protocol. Assessment included symptom history, muscle and joint palpation, familiar pain, joint sounds and altered jaw movement. A randomly selected sample was reassessed for examiner reliability. Mandibular movement was measured with a calibrated digital calliper. Pain free, maximum unassisted and assisted mouth opening, lateral excursion and protrusion were recorded in millimetres. Three measurements were averaged. Pain was recorded on an 11 point numerical rating scale. Functional limitation was assessed using the validated 20 item Jaw Functional Limitation Scale (JFLS-20). The global JFLS-20 score was calculated as the mean of the 20 items and ranged from 0 to 10. Higher scores indicated greater limitation. Saliva collection and biomarker analysis Unstimulated whole saliva was collected between 8:00 am and 10:00 am. For two hours before collection participants avoided food, drinks other than water, smoking, chewing gum, tooth brushing and mouthwash. After rinsing and resting for ten minutes saliva was collected into a sterile tube for five minutes. Blood contaminated samples were excluded. Samples were processed according to laboratory protocol. Staff were blinded to participant group. Validated colorimetric methods were used for malondialdehyde and total antioxidant capacity. Human specific enzyme linked immunosorbent assays measured interleukin 1 beta, interleukin 6 and matrix metalloproteinase 3. Tests were completed in duplicate with standards and quality controls. Study outcomes and control of bias The primary biochemical outcome was the difference in salivary malondialdehyde between cases and controls. The main functional outcome was maximum unassisted mouth opening. Secondary outcomes included the other biomarkers, mandibular measurements, pain intensity and JFLS scores. Cases and controls were recruited from the same source population and assessed using identical procedures. Clinical assessment was completed before biomarker results were available. Laboratory staff were blinded to clinical status. Age, sex, body mass index, smoking, oral inflammation, medication use, psychological distress, sleep disturbance and bruxism were recorded as potential confounders. Statistical analysis Data were analysed using IBM SPSS software version 31.0.2. Continuous variables were reported as mean and standard deviation or median and interquartile range according to distribution. Categorical variables were reported as frequencies and percentages. Cases and controls were compared using the Welch independent samples t test or Mann Whitney U test. Categorical variables were compared using the chi square test or Fisher exact test. Spearman correlation was used to examine biomarker relationships with maximum unassisted mouth opening, pain intensity and the JFLS-20 global score within the TMD group. The Benjamini Hochberg method controlled the false discovery rate across the 15 planned correlations. Separate multivariable linear regression models assessed each biomarker in relation to maximum unassisted opening and JFLS-20 score (Ohrbach et al., 2008). Models were adjusted for age, sex, body mass index, smoking and oral inflammation. Skewed biomarkers were log transformed. Effect estimates were reported with 95 percent confidence intervals. A two sided P value below 0.05 was considered statistically significant.

Participant flow and data completeness A total of 178 adults were screened. This included 90 potential TMD cases and 88 potential controls. Eighteen case candidates and 16 control candidates were excluded before enrolment. Seventy-two participants were enrolled in each group. Two participants in each group were excluded because their saliva samples did not meet assay quality criteria. The final analysis included 70 TMD cases and 70 controls. All 140 participants had complete demographic, clinical, JFLS-20 and biomarker data. No imputation was required. Participant flow and data completeness are presented in Table 1. Table 1. Participant flow and data completeness Stage TMD candidates Control candidates Total Assessed for eligibility 90 88 178 Excluded before enrolment 18 16 34 Enrolled 72 72 144 Invalid saliva sample 2 2 4 Included in complete case analysis 70 70 140 All 140 analysed records were complete for the planned clinical and biochemical variables. Participant characteristics and TMD profile The mean age was 34.0 years in TMD cases and 35.5 years in controls. Women represented 77.1 percent of each group. Age, sex, body mass index, smoking, oral inflammation and medicine use were similar between groups. Psychological distress, sleep disturbance and bruxism were more common among TMD cases. Among cases, 28 had muscular TMD, 20 had joint related TMD and 22 had combined TMD. The median symptom duration was 14.4 months with an interquartile range from 10.6 to 25.7 months. Participant characteristics are presented in Table 2. Table 2. Demographic and clinical characteristics Characteristic TMD cases n = 70 Controls n = 70 Standardised difference P value Age, years 34.0 ± 10.3 35.5 ± 7.7 -0.158 0.351 Body mass index, kg/m² 25.6 ± 3.6 24.6 ± 3.0 0.308 0.071 Female sex 54 (77.1) 54 (77.1) 0.000 1.000 Current smoking 6 (8.6) 6 (8.6) 0.000 1.000 Oral inflammation 4 (5.7) 7 (10.0) -0.159 0.532 Medication use 16 (22.9) 12 (17.1) 0.143 0.527 Psychological distress 20 (28.6) 6 (8.6) 0.514 0.004 Sleep disturbance 26 (37.1) 13 (18.6) 0.414 0.023 Bruxism 30 (42.9) 7 (10.0) 0.745 <0.001 Values are mean ± standard deviation or n (percent). Baseline P values are descriptive. Salivary biomarker comparison Median salivary MDA was higher in TMD cases than controls at 30.9 nmol/mL compared with 25.1 nmol/mL. This difference was statistically significant and showed a moderate to large standardised effect. Mean TAC was lower in cases but the difference was not significant. IL-1 beta and IL-6 showed small group differences. MMP-3 was higher in cases but did not reach the prespecified significance level. These findings supported a group difference for MDA. They did not show clear group differences for antioxidant capacity or the selected inflammatory and matrix degradation markers. The biomarker comparisons are presented in Table 3. Table 3. Comparison of salivary biomarkers between groups Biomarker Unit TMD cases n = 70 Controls n = 70 Effect size (Cohen’s d) P value Malondialdehyde nmol/mL 30.9 (25.2 to 38.2) 25.1 (20.8 to 29.5) 0.732 <0.001 Total antioxidant capacity µmol/L 836 ± 337 914 ± 318 -0.238 0.161 Interleukin 1 beta pg/mL 9.4 (7.3 to 15.3) 9.3 (7.5 to 12.1) 0.255 0.236 Interleukin 6 pg/mL 5.7 (4.6 to 7.2) 5.4 (4.4 to 7.0) 0.051 0.775 Matrix metalloproteinase 3 ng/mL 3.12 (2.44 to 4.12) 2.73 (2.12 to 3.77) 0.299 0.073 MDA, IL-1 beta, IL-6 and MMP-3 are median (interquartile range). TAC is mean ± standard deviation. Cohen's d values for skewed markers were calculated after log transformation. Abbreviations: MDA, malondialdehyde; TAC, total antioxidant capacity; IL, interleukin; MMP-3, matrix metalloproteinase-3. Mandibular function, pain and functional limitation All measured mandibular movements were lower in TMD cases. Pain intensity and JFLS-20 scores were higher in cases. These findings showed marked objective and self-reported mandibular dysfunction in the TMD group. The functional outcome comparisons are presented in Table 4. Table 4. Mandibular function, pain and JFLS-20 scores Outcome Unit TMD cases (n = 70) Controls (n = 70) Difference 95% CI P value Pain-free mouth opening mm 33.4 ± 5.5 44.9 ± 3.8 -11.55 -13.12 to -9.98 <0.001 Maximum unassisted mouth opening mm 38.5 ± 4.8 47.4 ± 3.6 -8.90 -10.32 to -7.47 <0.001 Maximum assisted mouth opening mm 42.7 ± 4.8 50.3 ± 3.8 -7.65 -9.10 to -6.20 <0.001 Right lateral excursion mm 7.8 ± 1.0 10.0 ± 1.2 -2.27 -2.65 to -1.90 <0.001 Left lateral excursion mm 7.9 ± 1.4 9.9 ± 1.1 -1.93 -2.35 to -1.52 <0.001 Protrusion mm 6.7 ± 0.9 8.6 ± 0.9 -1.94 -2.26 to -1.63 <0.001 Pain intensity 0 to 10 4.6 (3.8 to 5.5) 0.0 (0.0 to 0.0) 4.60 4.30 to 5.10 <0.001 JFLS-20 global score 0 to 10 3.2 (2.3 to 4.1) 0.3 (0.1 to 0.4) 2.88 2.47 to 3.46 <0.001 Movement variables are mean ± standard deviation. Pain and JFLS-20 are median (interquartile range). Negative movement differences indicate lower values in TMD cases. Differences were calculated as TMD cases minus controls. For pain intensity and JFLS-20 global score, 95% confidence intervals for differences between medians were estimated using stratified nonparametric percentile bootstrap resampling (100,000 iterations). Welch t tests were used for movement variables and Mann-Whitney U tests for pain intensity and JFLS-20. CI, confidence interval; JFLS-20, 20-item Jaw Functional Limitation Scale; TMD, temporomandibular disorders. Biomarker associations with mandibular dysfunction Within TMD cases, MDA had a negative correlation with maximum unassisted mouth opening. MDA had positive correlations with pain intensity and JFLS-20 global score. All three associations remained significant after false discovery rate correction. TAC, IL-1 beta, IL-6 and MMP-3 were not significantly related to functional outcomes after correction. The correlation results are presented in Table 5. Table 5. Correlations between biomarkers and functional outcomes in TMD cases Biomarker Outcome Spearman rho P value FDR q value Significant Malondialdehyde Maximum unassisted opening -0.431 <0.001 <0.001 Yes Malondialdehyde Pain intensity 0.553 <0.001 <0.001 Yes Malondialdehyde JFLS-20 global score 0.659 <0.001 <0.001 Yes Total antioxidant capacity Maximum unassisted opening 0.088 0.471 0.706 No Total antioxidant capacity Pain intensity -0.182 0.132 0.299 No Total antioxidant capacity JFLS-20 global score -0.142 0.242 0.454 No Interleukin 1 beta Maximum unassisted opening -0.292 0.014 0.053 No Interleukin 1 beta Pain intensity -0.009 0.942 0.989 No Interleukin 1 beta JFLS-20 global score 0.184 0.128 0.299 No Interleukin 6 Maximum unassisted opening 0.008 0.945 0.989 No Interleukin 6 Pain intensity 0.030 0.807 0.989 No Interleukin 6 JFLS-20 global score 0.002 0.989 0.989 No Matrix metalloproteinase 3 Maximum unassisted opening 0.004 0.974 0.989 No Matrix metalloproteinase 3 Pain intensity 0.118 0.331 0.552 No Matrix metalloproteinase 3 JFLS-20 global score 0.178 0.140 0.299 No The Benjamini Hochberg method was applied to 15 planned correlations. FDR means false discovery rate. Adjusted regression analysis After adjustment for age, sex, body mass index, smoking and oral inflammation higher MDA remained associated with lower maximum unassisted opening and a higher JFLS-20 score. None of the other biomarker models showed an independent association at the 0.05 level. The adjusted regression results are presented in Table 6. Table 6. Adjusted biomarker associations within TMD cases Outcome Biomarker Standardised beta 95% CI P value Adjusted R² Maximum unassisted opening Malondialdehyde -0.453 -0.697 to -0.209 <0.001 0.163 JFLS-20 global score Malondialdehyde 0.649 0.442 to 0.856 <0.001 0.398 Maximum unassisted opening Total antioxidant capacity 0.191 -0.067 to 0.448 0.144 0.014 JFLS-20 global score Total antioxidant capacity -0.174 -0.427 to 0.078 0.172 0.051 Maximum unassisted opening Interleukin 1 beta -0.224 -0.469 to 0.020 0.071 0.032 JFLS-20 global score Interleukin 1 beta 0.140 -0.104 to 0.383 0.256 0.043 Maximum unassisted opening Interleukin 6 0.003 -0.240 to 0.247 0.979 -0.020 JFLS-20 global score Interleukin 6 -0.013 -0.251 to 0.226 0.916 0.023 Maximum unassisted opening Matrix metalloproteinase 3 0.018 -0.227 to 0.262 0.887 -0.020 JFLS-20 global score Matrix metalloproteinase 3 0.154 -0.082 to 0.390 0.198 0.048 Each row represents a separate model adjusted for age, sex, body mass index, smoking and oral inflammation. Skewed biomarkers were log transformed.

This study examined salivary biomarkers and mandibular dysfunction in adults with TMD. The main finding was a higher salivary MDA level in TMD cases than in controls. MDA was also associated with reduced mouth opening, greater pain and greater jaw functional limitation. These associations remained after adjustment for age, sex, body mass index, smoking and oral inflammation. TAC, IL-1 beta, IL-6 and MMP-3 did not show clear independent associations with mandibular dysfunction. The findings therefore support a specific link between lipid peroxidation and clinical impairment rather than a general increase across all measured biomarkers. The participant characteristics require careful interpretation. Age, sex, body mass index, smoking, oral inflammation and medication use were similar between groups. This reduces concern that the main biomarker difference resulted from major imbalance in these variables. Psychological distress, sleep disturbance and bruxism were more common in TMD cases. These factors are consistent with the biopsychosocial nature of TMD. They may contribute to muscle activity, pain persistence and altered pain processing. However, they may also influence oxidative stress. Residual confounding is therefore possible. The higher MDA level in cases agrees with the finding of Omidpanah et al. (2020). That study also reported increased salivary lipid peroxidation in TMD. A recent systematic review and meta analysis found that salivary MDA was higher in people with TMD while TAC findings were inconsistent (Chauca Bajaña et al., 2026). The present result is biologically plausible. Mechanical loading and local hypoxia may increase reactive oxygen species. Lipid peroxidation may then damage cell membranes and promote inflammatory signalling. These processes may contribute to pain and impaired movement. Not all published evidence supports a difference in salivary MDA. Kazan et al. (2023) found no significant difference in salivary MDA between patients with disc displacement and healthy controls. Madariaga et al. (2021) also reported a different oxidative pattern in myogenous TMD. Differences in diagnostic groups may explain part of this inconsistency. The present sample included muscular, joint related and combined TMD. Differences in saliva collection, assay methods, symptom duration and sample size may also affect results. These points support cautious interpretation of MDA as a research marker rather than a diagnostic test. TAC was lower in TMD cases but the difference was not significant. TAC was also not related to mouth opening, pain or JFLS-20 score after false discovery rate correction. This finding agrees with Omidpanah et al. (2020) and with the inconsistent pooled evidence reported by Chauca Bajaña et al. (2026). TAC reflects the combined activity of several antioxidants. It may vary with diet, flow rate, oral health and collection conditions. A single measurement may not capture dynamic antioxidant responses. Compensatory antioxidant activity may also differ by TMD duration and phenotype. IL-1 beta and IL-6 did not differ significantly between cases and controls. Neither marker had a corrected association with functional outcomes. These findings do not support a strong systemic salivary cytokine signal in this sample. Kazan et al. (2023) also found no group difference in salivary IL-6. In contrast, some studies and reviews have reported raised inflammatory mediators in TMD or temporomandibular joint fluid (Alam et al., 2024; Soares et al., 2025). Saliva may not reflect local cytokine activity within the joint or masticatory muscles. Low concentrations, short half-lives and assay variation may reduce the ability to detect small effects. MMP-3 was higher in cases, but the difference did not meet the prespecified significance level. MMP-3 was not associated with function after correction or adjustment. Shoukri et al. (2019) reported an association between salivary MMP-3 and condylar changes in temporomandibular joint osteoarthritis. The present sample was defined by pain related TMD and was not restricted to osteoarthritis. This difference in phenotype may explain the weaker result. Matrix degradation markers may be more informative in structural joint disease than in a mixed clinical TMD group. TMD cases had markedly lower mandibular movement than controls. Pain free opening, maximum unassisted opening, maximum assisted opening, lateral excursions and protrusion were all reduced. Pain and JFLS-20 scores were also higher. These results directly address the functional objective and are consistent with the clinical features of symptomatic TMD. The agreement between measured movement and self reported limitation strengthens the evidence for clinically relevant dysfunction. The large group differences also show that functional assessment remains central even when biomarkers are studied. Within cases, MDA showed the clearest relationship with function. Higher MDA was related to lower maximum unassisted opening and higher JFLS-20 scores. It was also related to greater pain. The adjusted models retained the associations with mouth opening and JFLS-20. These findings suggest that oxidative damage may increase with the severity of mandibular dysfunction. Kuć et al. (2025) also reported relationships between oxidative balance and jaw functional limitation. However, the cross-sectional design does not establish direction. Greater pain and reduced movement may alter behaviour and stress responses. These changes could increase oxidative stress. Oxidative stress could also contribute to tissue sensitisation and functional impairment. Both pathways may occur together. The study has several strengths. TMD was identified with the DC/TMD protocol. Cases and controls came from the same source population. Saliva was collected at a standard time under controlled conditions. Clinical assessment occurred before biomarker results were known. Laboratory staff were blinded to group. Functional assessment included objective measurements, pain and JFLS-20. The analysis also used false discovery rate correction and adjusted models. These steps reduced the risk of chance findings and measured confounding. This study also has limitations. The case control design cannot establish temporal order or causality. A single saliva sample may not represent day-to-day biomarker variation. Salivary biomarkers can be affected by oral health, flow rate, diet, stress and medication. Some of these factors may remain uncontrolled. Psychological distress, sleep disturbance and bruxism differed between groups but were not included in the primary adjusted models. The TMD group included several clinical subtypes. Subtype specific effects may therefore have been diluted. The study was conducted at one hospital and this may limit generalisability. Multiple regression models were fitted in 70 cases. Small or unstable effects may have been missed. Measurement of local joint fluid or paired serum samples might have provided additional biological information. Finally, no diagnostic threshold was evaluated. MDA should not be used as a clinical diagnostic marker on the basis of these findings alone.

Adults with TMD had greater pain, greater jaw functional limitation and lower mandibular movement than controls. Salivary MDA was higher in cases and was associated with poorer mandibular function. TAC, IL-1 beta, IL-6 and MMP-3 showed weak or null associations. These findings support further study of oxidative lipid damage in TMD. Future multicentre longitudinal studies should use repeated saliva sampling and larger subtype specific groups. Studies should also assess psychological distress, sleep and bruxism in adjusted models. Paired saliva, serum and joint samples may help determine whether MDA reflects local disease activity or a wider oxidative response. Author Contributions Conceptualization: Abdul Wahab Jehangir, Muhammad Adnan, Saba Naveed Methodology: Muhammad Adnan, Abdul Wahab Jehangir, Irtaza Husain, Salman Ahmad Data Collection: Muhammad Adnan, Abdul Wahab Jehangir, Irtaza Husain Data Analysis and Interpretation: Abdul Wahab Jehangir, Irtaza Husain, Muhammad Adnan Manuscript Drafting: Muhammad Adnan, Irtaza Husain, Abdul Wahab Jehangir, Salman Ahmad, Naveed A. Khawaja, Saba Naveed, Hesham Rafiq Aziz Critical Review and Editing: Muhammad Adnan, Irtaza Husain, Abdul Wahab Jehangir, Salman Ahmad, Naveed A. Khawaja, Saba Naveed, Hesham Rafiq Aziz Supervision: Abdul Wahab Jehangir All authors have reviewed and approved the manuscript for publication.

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