The Role of Biomarkers in Temporomandibular Disorders: A Systematic Review
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. Characteristics of Included Studies
3.2. Summary of Key Findings
3.3. Risk of Bias
4. Discussion
5. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BMP | Bone morphogenetic protein |
CAT | Catalase |
CGRP | Calcitonin gene-related peptide |
CFHR3 | Complement factor H-related protein 3 |
CPN2 | Carboxypeptidase N catalytic chain |
CRP | C-reactive protein |
DD | Disc displacement |
DDwR | Disc displacement with reduction |
DDwoR | Disc displacement without reduction |
dNLR | Derived NLR |
ESR | Erythrocyte sedimentation rate |
GCS | Glucosamine–chondroitin sulphate |
HA | Hyaluronic acid |
HMGB1 | High-mobility group box 1 |
IASP | International Association for the Study of Pain |
IFN-γ | Interferon-gamma |
IL | Interleukin |
iNOS | Inducible nitric oxide synthase |
LLLT | Low-level laser therapy |
LMR | Lymphocyte-to-monocyte ratio |
MDA | Malondialdehyde |
MMP | Matrix metalloproteinase |
MMO | Maximum mouth opening |
NLR | Neutrophil-to-lymphocyte ratio |
OA | Osteoarthritis |
OPN | Osteopontin |
PGE2 | Prostaglandin E2 |
PLR | Platelet-to-lymphocyte ratio |
PRISMA | Preferred Reporting Items for Systematic Reviews and Meta-Analyses |
PRP | Platelet-rich plasma |
RDX | Radixin |
RCT | Randomized controlled trial |
SHA | Sodium hyaluronic acid |
SII | Systemic immune-inflammation index |
SOD | Superoxide dismutase |
SS | Stabilization splint |
TAC | Total antioxidant capacity |
TLR4 | Toll-like receptor 4 |
TMD | Temporomandibular disorders |
TMJ | Temporomandibular joint |
TMJ-ID | Temporomandibular joint internal derangement |
TNF | Tumour necrosis factor |
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---|---|---|---|---|---|
Tuerxun, P. et al. (2024) [10] | Case–control Observational China | Synovial fluid | 46 metabolites (fatty/organic/amino acids, sugars, amines, and others) | 11 females (41.91± 16.6 years) and 1 male (20 years) TMD: OA or DDwR, pain intensity not reported | OA showed distinct metabolic profiles from DDwR, with L-carnitine, taurine, and adenosine identified as potential biomarkers. TCA cycle and ferroptosis: OA pathogenesis and therapeutics. |
AlSahman, L. et al. (2024) [21] | Case–control Observational Saudi Arabia | Saliva | Cortisol | 132 patients divided in two groups (TMD: DDwoR vs. control), 18–40 years, pain intensity ≥ 4/10 | ↑ cortisol: Biomarker for specific TMD subtypes, especially in males with DDwoR. |
Ismah, N. et al. (2024) [22] | Cross-sectional Observational Indonesia | Saliva | IL-1β and C-reactive protein (CRP) | 77 females and 28 males, 26.4 years TMD with arthralgia, pain intensity not reported | Pain-related or joint TMDs with ↑ CRP > IL-1β. Both types were combined ↑ CRP < IL-1β. |
Tchivileva, I.E. et al. (2023) [23] | Cross-sectional Observational USA | Blood | Calcitonin gene-related peptide (CGRP) | 80 participants from 18 to 64 years Painful TMDs Average pain intensity of 53.2/100 | CGRP associated with age and Body Mass Index, but not chronic painful TMD. |
Aparna, N. et al. (2023) [24] | Case–control Observational India | Saliva | Cortisol | 50 patients divided in two groups, 18–45 years Painful or symptomatic TMD, pain intensity not reported | No statistically significant difference in salivary cortisol level between cases and controls. |
Kazan, D. et al. (2023) [25] | Cross-sectional Observational Turkey | Saliva, blood | IL-6, MDA, 8-OHdG | 44 patients, 14–40 years 27 with DDwR/DDwoR vs. 17 controls, pain intensity not reported | Strong positive correlation between pain, 8-OHdG, and IL-6. |
Ulmner, M. et al. (2022) [26] | Cross-sectional Observational Sweden | Synovial fluid/tissue | ILs, TNF-α | 101 patients, average age of 40.6 years TMD: DDwR, DDwoR, DJD, arthralgia Average pain intensity of 4/10 | IL-1β and TNF-α were significantly associated with TMJ palpation pain. TNF-α also correlated with subjective TMJ pain. IL-1β was linked to synovitis, which contributes to pain. |
Bayındır, S., et al. (2022) [27] | Cross-sectional Observational Turkey | Synovial fluid | Aggrecan, adiponectin, resistin, apelin, VEGF, and PGE2 | 41 patients, 12–72 years TMD: DDwR, DDwoR and OA Average pain intensity of 6/10 | Aggrecan and PGE2 are linked to localized TMJ pain and are elevated in joints with degenerative changes. |
Venkates h, S.B. et al. B. et al. (2021) [28] | Cross-sectional Observational India | Saliva | Cortisol | 187 females and 161 males, 18–23 years (20 with TMD vs. 20 controls) TMD: DDwR, DDwoR, arthralgia, and DJD, pain intensity not reported | Cortisol: strong association with stress and TMD severity. |
Ege, B. et al. (2021) [29] | Case–control Observational Turkey | Blood | OPN, CD44 | 71 patients, 18–57 years (54 with TMD vs. 17 controls) TMD: ID and subluxations, qualitative pain evaluated | ↓ OPN in TMD patients CD44 no statistical difference. |
Ege, B. et al. (2021) [30] | Case–control Observational Turkey | Blood | Asporin | 43 controls (31.30 ± 7.53) vs. 43 TMD (31.42 ± 13.24) TMD: DDwoR and OA, pain intensity not reported | Asporin significantly upregulated in TMD. |
Son, C. et al. (2021) [31] | Cross-sectional Observational Republic of Korea | Blood | ILs, IFN-γ, TNF-α, growth factors, PGE2, and THPO | 66 female participants (24.83 ±3.03 years) TMD with arthralgia Average pain intensity of 5.44/10 | TMD—higher pain intensity/duration and ↑ IL-8 and IgG levels link chronic pain and systemic inflammation. |
Ulmner, M. et al. (2020) [32] | Cross-sectional Observational Sweden | Synovial tissue | BMP, Epidermal Grow Factor (EGF), ILs and OPG, IFN-γ, IP, eotaxin | 51 females and 12 males (41.3 ± 15.1 years) TMD: DDwR (19 patients), DDwoR (44 patients) Pain intensity ≥ 4/10 (DDwoR>DDwR) | DDwoR: IP ↓, OPG ↓ EGF + IL-1 ra ↑ (female > male) sudden onset >delayed onset: BMP 4 ↑, Eotaxin ↑, IL-8 ↑. |
Omidpan ah, N. et al. (2020) [33] | Case–control Observational Iran | Saliva | MDA, TAC, and Catalase | 30 patients with TMD (30.7 ± 13.2 years) vs. 30 controls (29.16 ± 11.2 years) Painful TMD, pain intensity not reported | TMD: higher MDA levels, no changes in TAC and Catalase. |
Loreto, C. et al. (2020) [34] | Case–control Observational Italy | Synovial tissue | MMPs | 20 TMD vs. 10 controls DDwoR, pain intensity not reported | MMP-7 and MMP-9 overexpressed in DDwoR. |
Staniszewski, K. et al. (2019) [35] | Cross-sectional Observational Norway | Blood | Hemoglobin, cobalamin, albumin, PTH, vit D, creatinine, and potassium | 60 patients with TMD vs. 60 controls 20–69 years, mean age 45 years TMD with arthralgia, pain intensity not reported | Serum markers, including vitamin D, were not reliable for TMD diagnosis. |
Yapıcı, Y.G. et al. (2019) [36] | Cross-sectional Observational Turkey | Synovial fluid | Visfatin | 60 individuals (26.55 ± 8.3 years) with DDwoR and OA Pain intensity > 6/10 | ↑ Vistafin (OA) Positive correlation between pain and visfatin levels. |
Demir, C.Y. et al. (2018) [37] | Case–control Observational Turkey | Blood | 25(OH) vitamin D, PTH, calcitonin, calcium, phosphorus, magnesium | 50 TMD vs. 50 controls, mean age of 50 years, pain intensity not reported | 25(OH) vitamin D, calcitonin, calcium, magnesium, or phosphorus (no differences) ↑ PTH. |
Kaya, G.S. et al. (2018) [38] | Cross-sectional Observational Turkey | Synovial fluid | Chemerin | 60 patients (26,55± 8,3 years), 16–52 years TMD: ID and OA Average pain intensity of 70/100 | Positive correlation between pain and chemerin levels. |
Demir, C.Y. et al. (2018) [39] | Case–control Observational Turkey | Blood | MDA, Catalase superoxide dismutase (SOD), GSH | 32 patients TMD vs. and 32 controls, aged 16–50 years, pain intensity not reported | TMD: higher MDA and lower Catalase, SOD, GSH), no influence from age or gender. |
Lin, S.L., et al. (2015) [40] | Cross-sectional Observational Taiwan | Blood | Cortisol | 60 DDwoR patients, 37.7 ± 17.22 years vs. 80 patients DD 36.4± 13.08 years, pain intensity not reported | ↑ Cortisol in DDwoR: clinical indicator for distinguishing disc displacement disorders. |
Cevidanes, L.H. et al. H. et al. (2014) [41] | Case–control Observational USA | Synovial fluid and blood | MMPs, TIMPs, and several others | 24 females (39.9 ± 16 years) 12 OA (47.4 ± 16.1 years) vs. 12 controls (41.8 ± 12.2 years), pain intensity not reported | OA showed bone resorption: ANG and MMPs linked to bone apposition, while IL-6 and TNFα linked to bone resorption. |
Vos, L.M. et al. (2013) [42] | Cross-sectional case–control Observational Netherlands | Synovial fluid | Collagen type I/II, IL-1β, TNF-α, PGE2 | 30 OA patients (9 males, 21 females; 40.1 ± 15.3 years) vs. 10 controls (5 males, 5 females; 30.3 ± 10.8 years), pain intensity not reported | High collagen-II levels suggest it may be a useful marker for cartilage degradation. |
Albilia, J.B. et al. (2013) [43] | Case–control Observational Canada | Blood | BMPs, Alpha-2-heremans-schmid glycoprotein (AHSG) | 30 patients with DJD (hip patients— 64.6 ± 12.1, TMJ patients—41.6 ± 9.8) vs. 120 controls (mean age 38.8 years) Average pain intensity of 6.6/10 | ↑ BMP-2, BMP-4, ↓ AHSG levels. These markers may help guide treatment decisions. |
Slade, G.D. et al. D. et al. (2011) [44] | Case–control Observational USA | Blood | MCPs, MIPs, ILs, and several others | 344 females, 18–60 years TMD, pain intensity not reported | Localized TMD linked to IL-1ra and widespread TMD linked to IL-8. Positive correlation between pain intensity and MCP-1 levels. |
Lee, J.K. et al. (2010) [45] | Cross-sectional Observational USA | Synovial fluid | TNF-α and IL-6 | 24 TMD vs. 5 controls TMD symptomatic, pain intensity not reported | ↑ TNF-α and ↑ IL-6 in TMD without significant correlation. |
Sato, J. et al. (2007) [46] | Cross-sectional Observational Japan | Synovial tissue | IL-8 | 44 patients, 6 males and 38 females (mean age of 43 years, 17–84 years), with DDwoR vs. 7 controls Average pain intensity of 6/10 | ↑ IL-8 in TMD, no significant link to pain or inflammation severity. |
Yoshida, H. et al. (2007) [47] | Cross-sectional Observational Japan | TMJ specimens | CD34 | 20 DD and OA patients vs. 10 controls, 20–72 years, pain intensity not reported | ↑ CD34 in TMJ internal derangement linked to angiogenesis. |
Yoshida, K. et al. (2006) [48] | Cross-sectional Observational Japan | Synovial fluid | MMPs and aggrecanase | 35 patients (17–74 years, mean 36.6 years) with DDwR, DDwoR, and OA vs. 10 controls (16–44 years, mean 23.1 years) Average pain intensity of 60/100 (DDwR), 63.5/100 (DDwoR), and 65/100 in (OA) | ↑ MMP-9 in severe TMJ OA and disc displacement. ↑ MMP-2 and aggrecanase were elevated in early OA. Aggrecanase—marker for cartilage degradation. |
Yoshida, K. et al. (2005) [49] | Cross-sectional Observational Japan | Synovial fluid | Aggrecanase | 35 patients (17–74 years, mean 36.6 years) with TMD vs. 10 controls (16–44 years, mean 23.1 years) TMD: DDwR, DDwoR, and OA Average pain intensity of 61.7/100 | ↑ Aggrecanase in TMD, especially in severe OA and disc displacement. Aggrecanase—marker for cartilage degradation. |
Kaneyama, K. et al. (2004) [50] | Cross-sectional Observational Japan | Synovial fluid | ILs | 61 patients (52 females and 9 males) with DDwoR and OA vs. 7 controls, pain intensity not reported | ↑ IL-6 and ↑ IL-11 in joints with condylar bone changes: osseous degeneration. |
Kardel, R. et al. (2003) [51] | Cross-sectional Observational Sweden | Synovial tissue | ILs, TNF-α, IFN-γ, TGF-β1,2,3, CD68, CD45RO, proliferating cell nuclear antigen | 39 patients (19 with arthralgia: 18–66 years and 20 with OA: 26–62 years) Average pain intensity of 5.6/10 in painful clicking and 6.7 in OA | OA joints: ↑ IL-1α, ↑ IL-1β, ↑ IFN-γ, ↑ IL-1ra, ↑ CD68+ macrophages, ↑ inflammation, and ↑ immune activity. |
Nagai, H. et al. (2003) [52] | Cross-sectional Observational Japan | Synovial tissue | iNOS, Fas, CD68, and ssDNA | 33 patients with TMD (ID and OA), 17–75 years vs. 33 controls, 17 to 54 years old, pain intensity not reported | ↑ iNOS, ↑ CD68, ↑ Fas, ↑ ssDNA were linked to synovial changes in TMD disease progression. |
Srinivas, R. et al. (2001) [53] | Cross-sectional Observational Canada | Synovial fluid | MMPs | 44 TMD with ID patients (33 females and 11 males) with a mean age of 36 years (16–76 years), pain intensity not reported | ↑ MMP-1, ↑ MMP-2, ↑ MMP-8, ↑ MMP-9 ↑, MMP-13 in mild TMJ-ID—active collagen degradation. |
Tanaka, A. et al. (2001) [54] | Cross-sectional Observational Japan | Synovial fluid | MMPs | 38 DDwR, DDwoR, and OA patients, 15–69 years (34.8 ± 14.7 years), vs. 20 controls, 22 to 47 years (26.8 ± 3.7 years), pain intensity not reported | ↑ MMP-2 and ↑ MMP-9 in DDwoR>DDwR—diagnostic markers. |
Murakami, K.I. et al. (1998) [55] | Cross-sectional Observational Japan | Synovial fluid | PGE2, HA, C4S, and C6S | 15 females with painful TMD, mean age of 36.7 years Average pain intensity from 5.1/10 to 6.6/10 | ↑ PGE2 linked to pain scores ↑ C4S and ↑ C6S linked to TMJ degeneration—markers of proteoglycan breakdown pain-related joint changes. |
Kubota, E. et al. (1998) [56] | Cross-sectional Observational Japan | Synovial fluid | MMPs and ILs | 22 DDwoR and OA patients vs. 11 controls, pain intensity not reported | IL-1β ↑ (DDwoR), IL-1β ↑ (OA), IL-6 ↑ (OA) —catabolic markers linked to cartilage degradation and pain in TMD. |
Kubota, E. et al. (1997) [57] | Case–control Observational USA | Synovial fluid | IL-1β, MMP, TNF-α | 22 TMD with OA patients, 15–77 years vs. 15 controls, 18–66 years, pain intensity not reported | ↑ IL-1β in TMD (osteolytic changes TMJs) ↑ MMP-3 linked to cartilage degradation —early markers of TMJ deterioration and pain. |
Reference | Study Type/ Country | Type of Sample | Biomarkers | Population Characteristics/Treatment | Results |
---|---|---|---|---|---|
Thamer, S.R. and Diajil, A.R. (2024) [8] | Non-RCT Iraq | Saliva | Matrix metalloproteinases (MMPs) | 32 females and 20 males, 18–55 years with TMD resistant to conservative therapy Intra-articular HA (30 patients) and PRP (22 patients) treatment | MMP-2 and MMP-9 positively correlated with pain and joint click/negatively with mouth opening. HA and PRP therapies reduce inflammation and improve TMD symptoms. |
Cho, I.S. et al. (2024) [9] | Cross-sectional Observational South Korea | Blood | Total protein, neutrophils, lymphocytes, monocytes, platelets, and ratios | 154 patients, 30.2 ± 10.6 years TMD with arthralgia Average pain intensity of 4/10 | 69.5% showed significant pain improvement. Hematologic markers, particularly low hemoglobin, may help predict long-term treatment outcomes in TMD. |
Shao, B. et al. (2023) [58] | Cross-sectional Observational China | Synovial fluid | HMGB1, interleukins (ILs), PGE2, RAGE, TLR4, and iNOS | Two TMD groups: OA: 77% females, 40.36 ± 9.67 years ID: 70% females, 31.5 ± 10.62 years Intra-articular HA injection 1x/week for 2 weeks Average pain intensity of 5.97/10 in OA and 3.6/10 in DD | High levels of biomarkers, OA > DD HMGB1 levels, pain scores, and jaw dysfunction scores improved after HA treatment. |
Kim, Y. et al. (2023) [59] | Cross-sectional Observational South Korea | Blood | ILs, ESR, high-sensitivity C-reactive protein (hs- CRP), cortisol, ACTH, norepinephrine, and epinephrine. | 63 females, 24.84 ± 3.00 years, TMD with arthralgia Conservative treatment Hematological analysis at 3 and 6 months post-treatment. | Significant pain improvements (≥2/10) of 64.29%, 41.67%, and 66.67% in normal-, short-, and long-sleep group, respectively. ↑ IL-1β, ↑ IL-4, ↑ IL-8, and ↑ IL-17 showed sufficient strength in predicting significant pain improvement with long-term TMD treatment. |
Liu, X. et al. (2022) [60] | Cross-sectional Observational China | Synovial fluid | 1714 proteins in the cytosol (43%), plasma membrane (31%), and extracellular space (25%) | 95 females and 14 males, 21.31 ± 7.95 years with TMD DDwoR Conservative treatment or disc reposition | ↑ ACACB during pain, ↑ HADHA in bruxism, ↑ TGFB1-impaired bone formation. Higher pain levels related to ↑ radixin, ↑ LCP1, ↑ CPN2, ↓ CFHR3, ↓ Factor 11, ↓ INADL, ↓ MBL2. |
Zwiri, A.M. et al. (2022) [61] | RCT Malaysia | Blood | hs-CRP, ILs | 12 males and 20 females, 20.9 years with painful TMD Conservative treatment (CT), low-level taser therapy (LLLT), and a combination of both | IL-8 may serve as a potential biomarker for TMJ pain: hs-CRP ↑ (LLT, C) ≈ (CT) IL-6 ↑ (LLLT, CT) ↓ (C) IL-8 ↓ (LLLT) ↑ (CT, C); no significant correlation between pain intensity and biomarker levels except for IL6 at baseline and after treatment. |
Alajbeg, I.Z. et al. (2020) [62] | RCT Croatia | Saliva | Oxidative stress | 20 females, 36.1 ± 11.95 years, TMD with arthralgia Oral splint or placebo for 6 months Average pain in the last 10 days > 30/100 | Splint improved pain and depressive symptoms in TMD with associated reductions in oxidative stress. |
Ganti, S. et al. (2018) [63] | RCT India | Synovial fluid | ILs, TNF-α, PGE2 | 30 males and 30 females, 20.9 years with DDwR Treated with glucosamine–chondroitin sulphate, tramadol, or sodium hyaluronate | Treatments improved mouth opening and pain in all groups, with associated reductions in inflammatory markers IL-1β, TNF-α, PGE2, and IL-6. |
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Soares, J.M.; Carneiro, B.D.; Pozza, D.H. The Role of Biomarkers in Temporomandibular Disorders: A Systematic Review. Int. J. Mol. Sci. 2025, 26, 5971. https://doi.org/10.3390/ijms26135971
Soares JM, Carneiro BD, Pozza DH. The Role of Biomarkers in Temporomandibular Disorders: A Systematic Review. International Journal of Molecular Sciences. 2025; 26(13):5971. https://doi.org/10.3390/ijms26135971
Chicago/Turabian StyleSoares, Joana Maria, Bruno Daniel Carneiro, and Daniel Humberto Pozza. 2025. "The Role of Biomarkers in Temporomandibular Disorders: A Systematic Review" International Journal of Molecular Sciences 26, no. 13: 5971. https://doi.org/10.3390/ijms26135971
APA StyleSoares, J. M., Carneiro, B. D., & Pozza, D. H. (2025). The Role of Biomarkers in Temporomandibular Disorders: A Systematic Review. International Journal of Molecular Sciences, 26(13), 5971. https://doi.org/10.3390/ijms26135971