Tissue Inhibitor Of Metalloproteinase-1 In Patients Research Articles

Biological markers of endothelial dysfunction and fibrosis, macro- and microcirculation alterations in patients with obstructive and nonobstructive coronary artery disease and diabetes mellitus

Abstract Aim of the study To analyze the association of biological markers levels of endothelial dysfunction and fibrosis with macro- and microcirculation alterations in patients with obstructive and nonobstructive coronary artery disease (CAD) and type 2 diabetes mellitus (DM). Methods 52 patients with CAD were enrolled and divided into 4 groups: 19 patients with nonobstructive CAD (1–49% stenosis) without DM (1 group: 4 men, age 64.89±7.61, body mass index (BMI) 28.14±3.69 kg/m2); 13 patients with obstructive CAD (≥50% stenosis) without DM (2 group: 9 men, age 66.92±7.02, BMI 30.4±5.91 kg/m2); 10 patients with obstructive CAD (3 group: 4 men, age 63.4±10.37, BMI 31.7±4.81kg/m2) and 10 patients with nonobstructive CAD with DM (4 group: 3 men, age 64.6±5.32, BMI 33.74±3.25 kg/m2). Patients were matched for age, sex and BMI. All patients underwent coronary angiography or coronary computed tomography angiography. Biological markers levels (E-selectin, ng/ml; tissue inhibitor of metalloproteinase 1 (TIMP-1), ng/ml) were measured using ELISA. To determine arterial damage in both macro- and microcirculation, digital reactive hyperemia photoplethysmography were performed. Endothelial function of small (Occlusion Index, OI) and large vessels (Phase Shear, PS, ms) were analyzed. Vascular remodeling of aorta (Stiffness Index, aSI, m/s) and arterioles (Reflection Index, RI, %) were studied. Results The elevation of E-selectin (1 – 21.6 [18.7; 30.4]; 2 – 31.5 [20.1; 36.9]; 3 – 42.25 [29.9; 55.3]; 4 – 42.1 [33.1; 46.5]) and TIMP-1 (1 – 416 [376; 481]; 2 – 478 [381; 539]; 3 – 534 [490; 579]; 4 – 590 [520; 782]) levels were found in all groups. Statistical analysis revealed significant differences between TIMP-1 (p1–3=0.004; p1–4=0.003) and E-Selectin (p1–3=0.013; p1–4=0.01) levels. Remodeling of large vessels was detected only in patients with obstructive CAD without DM and nonobstructive CAD with DM (2 – aSI, 9.05 [7.08; 10.58]; 3 – aSI, 8.2 [7.6; 11]). Patients in all groups had endothelial dysfunction of large vessels (PS, 1 – 5.1 [1.75; 7.75]; 2 – 6.45 [5.53; 9.03]; 3 – 7.65 [13.4; 9.5]; 4 – 4.6 [0.7; 8.1] and arterioles (IO; 1 – 1.5 [1.38; 1.78]; 2 – 1.4 [1.26; 1.53]; 3 – 1.4 [1.2; 1.7]; 4 – 1.3 [1.2; 2.0]). Structural disorders of arterioles were found in all groups, except for patients with obstructive CAD without DM (RI, 1 – 36.95 [23.4; 52.65]; 2 – 28.25 [23.35; 53.75]; 3 – 41.15 [26.5; 55]; 4 – 44.7 [20; 54.5]. The data did not show significant differences between the study groups. Conclusions The data showed that biological markers levels of endothelial dysfunction and fibrosis were increased in all groups. Significant differences revealed between the levels of E-selectin and TIMP-1 in patients with nonobstructive CAD without DM and patients with CAD and DM, regardless of the degree of stenosis. All patients had functional changes of large vessels and arterioles regardless of the severity of coronary artery atherosclerosis and presence of DM. Funding Acknowledgement Type of funding sources: None.

Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis

BackgroundWe previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy.MethodsThe relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study).ResultsIn the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months.ConclusionWe herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) as a prognostic biomarker in gastrointestinal cancer: a meta-analysis

BackgroundTissue inhibitor of metalloproteinase 1 (TIMP-1) has recently been shown to be dependent on or independent of Matrix metalloproteinases (MMPs) in its roles in tumorigenesis and progression. This appreciation has prompted various studies assessing the prognostic value of TIMP-1 in patients with gastrointestinal cancer, however, the conclusions were still inconsistent. The aim of this study was to assess the prognostic value of TIMP-1-immunohistochemistry (IHC) staining and pretreatment serum/plasma TIMP-1 level in gastrointestinal cancer survival as well as the association between TIMP-1 and clinicopathologic features.MethodsThe meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration NO. CRD42020185407) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. A highly sensitive literature search was performed in electronic databases including PubMed, EMBASE and the Cochrane Library. Heterogeneity analysis was conducted using both chi-square-based Q statistics and the I2 test. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the prognostic value of TIMP-1 using the fixed-effects model. Odds ratios (ORs) with 95% CIs were calculated to evaluate the associations between TIMP-1 and clinicopathological characteristics. The meta-analysis was conducted using STATA 12.0 software.ResultsA total of 3,958 patients from twenty-two studies were included in the meta-analysis. Elevated TIMP-1 levels were significantly associated with poor survival in gastrointestinal cancer (TIMP-1-IHC staining: HR = 2.04, 95% CI [1.59–2.61], I2 = 35.7%, PQ = 0.156; pretreatment serum/plasma TIMP-1 levels: HR = 2.02, 95% CI [1.80–2.28], I2 = 0%, PQ = 0.630). Moreover, clinicopathological parameter data analysis showed that elevated TIMP-1 levels were significantly associated with lymph node metastasis (N1/N2/N3 vs N0: OR = 2.92, 95% CI [1.95–4.38]) and higher TNM stages (III/IV vs I/II: OR = 2.73, 95% CI [1.23–6.04]).ConclusionBoth TIMP-1-positive IHC staining and high serum/plasma TIMP-1 levels are poor prognostic factors for the survival of gastrointestinal cancer. In addition, TIMP-1 overexpression was correlated with more advanced clinicopathological features.

Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis

BackgroundTargeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).MethodsA large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples (n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study).ResultsOur proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers).ConclusionsWe have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.

TIMP-1 in patients with cirrhosis: relation to liver dysfunction, portal hypertension, and hemodynamic changes

Objective. Cirrhotic portal hypertensive patients often develop hemodynamic complications and the diagnosis is often based on liver biopsy and measurements of the hepatic venous pressure gradient (HVPG). Potential noninvasive biomarkers for the severity of cirrhosis are the matrix metalloproteinase and their specific inhibitors such as tissue inhibitor of metalloproteinases-1 (TIMP-1). The aim of the study was to investigate TIMP-1 levels in cirrhosis in relation to the degree of liver dysfunction, portal hypertension, and hemodynamic changes. Materials and methods. We retrospectively studied 84 patients with cirrhosis and 14 controls without liver disease. All individuals underwent a liver vein catheterization with a hemodynamic assessment. TIMP-1 was determined in arterial and hepatic venous plasma using an MAC-15 TIMP-1 ELISA. Results. Hepatic venous concentrations of TIMP-1 were significantly increased in patients compared to controls: 336 (166) ng/ml versus 145 (100) (median/IQ range) (p < 0.001) with a progressive increase throughout the Child classes (p < 0.001). Circulating TIMP-1 correlated significantly with indocyanine green clearance (r = –0.44, p < 0.0001), Child Turcotte score (r = 0.50, p < 0.0001), HVPG (r = 0.40, p < 0.0001), mean arterial pressure (r = –0.29, p = 0.008), and systemic vascular resistance (r = –0.23, p = 0.03). Receiver operating characteristic curve analysis enabled us to establish cutoff values for TIMP-1 with regard to portal hypertension. Conclusions. TIMP-1 is significantly increased in patients with cirrhosis and correlates with the severity of the disease, degree of portal hypertension, and vasodilatory state. TIMP-1 is therefore a promising new noninvasive marker to predict hemodynamic-related complications in cirrhosis.

Plasma TIMP-1 in patients with metastatic colorectal cancer treated with first-line oxaliplatin-based therapy with or without cetuximab: Results from the Nordic VII study.

e14710 Background: Plasma Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) is a biomarker in patients with metastatic colorectal cancer (mCRC). TIMP-1 inhibits matrix metalloproteinases and has tumor promoting functions. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based but not oxaliplatin-based treatment in patients with mCRC. Based on our prior studies, we here tested the hypothesis that high pretreatment plasma TIMP-1 correlate with short overall survival (OS) and short progression-free survival (PFS) but not response rate (RR) in patients with mCRC included in the NORDIC VII Study in which patients received oxaliplatin-based therapy. Methods: In the NORDIC VII Study patients were randomized to: A) Nordic FLOX; B) Nordic FLOX + cetuximab or C) Nordic FLOX intermittently + cetuximab continuously. Plasma samples for TIMP-1 analysis were available from 426 patients. Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic ELISA. Results: The three study populations were comparable and not different from the total intention to treat population. The median pretreatment plasma TIMP-1 was 269 ng/mL (58-1318 ng/mL). KRAS mutated in 149 patients (35%). There was no interaction between treatment arms and pretreatment plasma TIMP-1 either for PFS (p = 0.16) or OS (p = 0.64). High pretreatment plasma TIMP-1 was associated with shorter PFS (HR=1.22, 1.07-1.39, p=0.003) and shorter OS (HR=1.55, 1.36-1.80, p&lt;0.0001). RR did not correlate significantly to pretreatment plasma TIMP-1 (OR=1.16, 0.91-1.49, p=0.22). Multivariate analysis (TIMP-1, Köhne index, KRAS and BRAF status, CRP, CEA, age, gender) demonstrated that high pretreatment plasma TIMP-1 was not an independent biomarker of PFS (HR=1.06, 0.88-1.28, p=0.52) or OS (HR=1.19, 0.96-1.47, p=0.11). Conclusions: Plasma TIMP-1 is a prognostic biomarker in patients with mCRC treated with 1st line oxaliplatin-based therapy +/- cetuximab. A predictive effect of plasma TIMP-1 could only be estimated for cetuximab treatment, and no significant treatment by marker interaction was observed.

Local and Systemic Expressions of MMP-9, TIMP-1 and PAI-1 in Patients Undergoing Surgery for Clinically Suspected Appendicitis

Background/Aims: To examine, compare and correlate the expressions of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) in appendiceal tissue and pre- and postoperative blood samples in patients undergoing surgery for clinically suspected appendicitis. Methods: Fifty-seven patients with complete tissue and blood samples were included and divided into groups of noninflamed appendix/lymphadenitis (n = 7), phlegmonous appendicitis (n = 30), gangrenous appendicitis (n = 11) and perforated appendicitis (n = 9). The protein expressions were assessed with ELISAs. The local expressions of MMP-9, TIMP-1 and PAI-1 were correlated with the systemic expressions at the time of surgery while the systemic individual differences between surgery and recovery were compared. Results: There was a positive correlation between tissue and plasma PAI-1 (p < 0.05). The individual differences for plasma MMP-9 and PAI-1 were statistically nonsignificant, while they were higher for TIMP-1 in patients with perforated appendicitis compared with phlegmonous (p < 0.0001) and gangrenous appendicitis (p < 0.01). Conclusions: Plasma PAI-1 reflected the levels in appendiceal tissue at the time of surgery. Systemic TIMP-1 could have the potential of distinguishing perforated from nonperforated appendicitis.

Serum Tissue Inhibitor of Metalloproteinases 1 (TIMP-1) Predicts Organ Recovery from Delayed Graft Function after Kidney Transplantation from Donors after Cardiac Death

Donors after cardiac death (DCD) have recently become an important source of renal transplants to alleviate the shortage of renal grafts in kidney transplantation (KTx), although DCD kidneys often have complications associated with a delayed graft function (DGF). A microarray-based approach using renal biopsy samples obtained at 1 h after KTx from DCD identified the tissue inhibitor of metalloproteinases 1 (TIMP-1) gene as a potential predictive marker for DGF. The current study measured serum TIMP-1 in patients undergoing KTx and analyzed the time course after KTx. The average serum TIMP-1 level before KTx was 240 ± 10 ng/ml (n = 34). In patients undergoing KTx from a living donor (n = 23), the serum TIMP-1 levels showed no increase after KTx (POD1: 226 ± 12, POD2: 211 ± 12, and POD3: 195 ± 10 ng/ml), but in one case, the only patient who required post-KTx HD due to DGF, the level on POD1 was the highest among subjects (361 ng/ml). In contrast, patients undergoing KTx from DCDs (n = 11), the serum TIMP-1 levels increased rapidly after a KTx (POD1: 418 ± 32, POD2: 385 ± 42, and POD3: 278 ± 25 ng/ml). However, two patients who avoided post-KTx HD due to the immediate function of the graft did not show increased levels (<370 ng/ml) on either POD1 or POD2. The peak serum TIMP-1 values appeared to correlate to the post-KTx dialysis period. Furthermore, the increment of serum TIMP-1 on the early POD was found to be predictive of immediate or delayed function of the grafts. These data suggest that monitoring of serum TIMP-1 levels allow the prediction of graft recovery and the need for HD after a KTx from a DCD.

Correlation of Plasma MMP-1 and TIMP-1 Levels and the Colonic Mucosa Expressions in Patients with Ulcerative Colitis

Background. Both plasma and mucosal levels of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) have been shown to be independently correlated with ulcerative colitis (UC), but their relationship with each other and to disease severity remains unclear. This study aims to evaluate the relationship between colonic mucosal and plasma levels of MMP-1 and TIMP-1 with each other and with the severity of ulcerative colitis (UC). Methods. Colonic mucosal lesions and venous blood samples were collected from 30 patients with UC and 15 normal subjects. Real-time reverse transcription-PCR and immunohistochemistry were used to determine colonic mucosal MMP-1 and TIMP-1 expression; ELISA was used to measure plasma levels of MMP-1 and TIMP-1. Results. Expression of colonic mucosal and plasma MMP-1 and TIMP-1 in patients with UC was significantly higher than that of controls (P < .05), and was positively correlated with disease severity (P < .05). Plasma MMP-1 and TIMP-1 levels were well correlated with their corresponding expression in colonic mucosa (P < .05, r = 0.805 and 0.908). Conclusion. Plasma MMP-1 and TIMP-1 levels reflect their colonic mucosal expression to some extent in patients with UC. Plasma MMP-1 and TIMP-1, in particular, demonstrate the potential to become biomarkers to clinically diagnose UC, predict its severity, and guide further therapy.

Comparative studies of tissue inhibitor of metalloproteinases-1 in plasma, serum and tumour tissue extracts from patients with primary colorectal cancer

Objective. We have recently shown that preoperative plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) levels are significantly associated with prognosis of colorectal cancer patients. In addition, we have shown that measurement of plasma TIMP-1 yields information on specificity and sensitivity, which could be used for early detection of colorectal cancer. However, it is not clear whether the increased plasma TIMP-1 levels in colorectal cancer patients are derived from the tumour tissue itself in which it is mainly expressed by the stromal cells located in the vicinity of the cancer cells. The purpose of this study was to examine the association between blood TIMP-1 levels and tumour tissue TIMP-1 levels in colorectal cancer patients. Material and methods. Preoperative EDTA plasma, citrate plasma and serum, as well as tumour tissue extracts from 49 colorectal cancer patients were measured with a TIMP-1 ELISA that measures total TIMP-1 levels (non-complexed and complexed TIMP-1). Results. The median TIMP-1 level in the 49 tumour extracts was 18.7 ng/mg proteins (range 3.5–152.0 ng/mg protein). The median TIMP-1 value was 133.5 ng/ml (range 58.1–559.0 ng/ml) in EDTA plasma, 130.2 ng/ml (range 57.0–572.0 ng/ml) in citrate plasma and 207.2 ng/ml (range 72.6–828.0 ng/ml) in serum. No significant correlations were found between TIMP-1 content in the tumour extracts and in blood.However, EDTA and citrate plasma TIMP-1 levels (r =0.75; p <0.0001) as well as EDTA plasma and serum TIMP-1 levels (r=.064; p <0.0001) were highly correlated. Conclusions. The lack of correlation between tumour tissue TIMP-1 and blood levels of TIMP-1 suggests that other sources than the tumour tissue itself may contribute to the increased levels of plasma TIMP-1 in patients with colorectal cancer. However, degradation of cell membranes, rapid secretion into the blood stream and other factors may be responsible for the observed lack of association between TIMP-1 concentrations in blood and tumour tissue extracts.

Plasma TIMP-1 in patients with colorectal adenomas: a prospective study

Colorectal cancer patients have increased plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1). However, it remains unresolved whether colorectal adenomas are associated with increased plasma TIMP-1. Plasma TIMP-1 levels were determined using an immunoassay in 121 patients prospectively enrolled from surveillance colonoscopy programmes. TIMP-1 levels were correlated to various clinicopathological parameters. No significant associations were found between plasma TIMP-1 and size, macro- or microscopic morphology or grade of dysplasia of the adenomas. No significant differences in TIMP-1 levels were found between patients with adenomas ( n=36), hyperplastic polyps ( n=12) or no pathology ( n=68) of the large intestine. However, patients with colonic ( n=3) or rectal ( n=2) adenocarcinomas had significantly increased TIMP-1 levels ( P=0.02). The present study demonstrates that measurement of plasma TIMP-1 cannot be used for the identification of adenomatous or hyperplastic polyps of the large intestine.

Effect of Plasma Exchange on Serum Tissue Inhibitor of Metalloproteinase 1 and Cytokine Concentrations in Patients with Fulminant Hepatitis

Aims: The present study assessed whether the serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and cytokines are altered in patients with fulminant hepatitis and whether plasma exchange affects these concentrations. Methods: Fifteen patients with fulminant hepatitis, 14 patients with severe acute hepatitis, and 20 healthy controls were included in this study. The serum levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), transforming growth factor beta (TGF-β), and TIMP-1 were determined in all patients upon hospital admission and before and after a single course of plasma exchange in the patients with fulminant hepatitis. Results: Ten out of the 15 patients with fulminant hepatitis and all patients with severe acute hepatitis survived. Serum TNF-α, IL-6, TGF-β, and TIMP-1 levels in patients with fulminant hepatitis were significantly higher than the levels in patients with severe acute hepatitis (p < 0.01). IL-1β was not detectable in either group. Plasma exchange reduced the increased serum concentrations of TNF-α, IL-6, TGF-β, and TIMP-1 in patients with fulminant hepatitis (p < 0.01). Conclusions: These data suggest that increased serum levels of TIMP-1 and cytokines may reflect severe hepatic inflammation and that plasma exchange is an effective therapy to reduce these levels.

Temporal patterns of stromelysin‐1, tissue inhibitor, and proteoglycan fragments in human knee joint fluid after injury to the cruciate ligament or meniscus

Stromelysin-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and proteoglycan fragments were quantified in knee synovial fluid samples in a cross-sectional study of patients who had injury to the anterior cruciate ligament or the meniscus. The average concentrations of stromelysin-1 and TIMP-1 increased 25-fold and 10-fold within the first day after the trauma, respectively, and the concentration of proteoglycan fragments increased 4-fold. From approximately 1-6 months after injury, the levels of these markers were higher after injury to the cruciate ligament than after injury to the meniscus. From 6 months to 18 years after trauma, however, the levels of stromelysin-1 and TIMP-1 in patients who had an injury to the ligament were the same as the levels in patients who had a meniscal lesion, but the levels were increased compared with those for a reference group of healthy volunteers. The molar balance of stromelysin-1 to TIMP-1 in synovial fluid in both groups of injured joints changed from a balance representing an excess of free inhibitor in the normal joint to one representing an excess of free enzyme in the injured joint. The increased release of these markers to joint fluid both early and late after trauma may be caused by a change in the loading patterns in the knee with an injured ligament or meniscus or by synovitis induced by bleeding. The increased release may be associated with the frequent development of posttraumatic osteoarthritis in patients with these injuries.