Editorial Commentary: Serum Cartilage Oligomeric Matrix Protein Appears to Be the Most Useful Biomarker for Tracking Early Osteoarthritis of the Knee in Anterior Cruciate Ligament Deficient Patients (But May Also Reflect Synovitis).

Owing to chondral or meniscal pathology sustained at the time of injury, patients who sustain anterior cruciate ligament injury are at risk of knee osteoarthritis (OA). Thus, recognition of early OA is critical. Detection of joint space narrowing on radiography has been described as outdated, and furthermore, the different descriptions of the Kellgren-Lawrence criteria have an impact on the classification of OA of the lowest grade (Kellgren-Lawrence grade ≥ 1). Serum cartilage oligomeric matrix protein (COMP) may allow detection of early OA in patients with anterior cruciate ligament deficiency because significantly higher levels have been observed in patients with early OA than in patients with non-early OA. Serum COMP appears to be the most useful of the biomarkers studied. Prior studies have shown correlations with OA in animal models and via magnetic resonance imaging evaluation. However, I would be hesitant about widespread use. It is possible that the serum COMP level reflects not only cartilage damage but also synovitis. This may be particularly misleading in patients with diagnoses of rheumatologic disorders and/or undiagnosed genetic HLA-B27 variants.

Serum Cartilage Oligomeric Matrix Protein Detects Early Osteoarthritis in Patients With Anterior Cruciate Ligament Deficiency.

PURPOSE: To investigate the ability of serum cartilage oligomeric matrix protein (COMP) to detect early osteoarthritis (OA) (International Cartilage Research Society [ICRS] grade 1 or 2 cartilage lesions) in patients with anterior cruciate ligament (ACL)-deficient patients. METHODS: Patients with an ACL injury of Kellgren-Lawrence grade 0 or 1 were enrolled. Serum samples for COMP measurement were obtained before surgery. The cartilage surfaces of 6 compartments were classified using the ICRS grading system. The patients were divided into groups with and without early OA according to the cartilage findings and diagnostic criteria for early OA. RESULTS: In total, 98 patients (mean age 23.7 years; range 12 to 49) were included, with 30 patients (30.6%) in the early OA group and 68 (69.4%) in the no early OA group. The 2 groups significantly differed in age, body mass index, preoperative Tegner activity scale, and serum COMP level. The cutoff value of serum COMP for the presence of early OA arthroscopic cartilage lesions was 152.0 ng/mL. Multiple logistic regression analysis revealed age (odds ratio 1.09; 95% confidence interval [CI] 1.02 to 1.16; P = .01) and serum COMP (odds ratio 1.02; 95% CI 1.01 to 1.04; P < .001) to be independent factors for the presence of early OA arthroscopic cartilage findings. CONCLUSIONS: The incidence of early OA arthroscopic cartilage findings was ∼30% in patients with ACL deficiency, and serum COMP levels were significantly higher in the early OA group than in the no early OA group. The optimum cutoff value for serum COMP was 152 ng/mL. Serum COMP can be used to detect early cartilage change in patients with ACL deficiency. LEVEL OF EVIDENCE: Ⅲ, retrospective comparative study.

Tibiofemoral articular cartilage composition differs based on serum biochemical profiles following anterior cruciate ligament reconstruction.

OBJECTIVE: Biochemical joint changes contribute to posttraumatic osteoarthritis (PTOA) development following anterior cruciate ligament reconstruction (ACLR). The purpose of this longitudinal cohort study was to compare tibiofemoral cartilage composition between ACLR patients with different serum biochemical profiles. We hypothesized that profiles of increased inflammation (monocyte chemoattractant protein-1 [MCP-1]), type-II collagen turnover (type-II collagen breakdown [C2C]:synthesis [CPII]), matrix degradation (matrix metalloproteinase-3 [MMP-3] and cartilage oligomeric matrix protein [COMP]) preoperatively to 6-months post-ACLR would be associated with greater tibiofemoral cartilage T1ρ relaxation times 12-months post-ACLR. DESIGN: Serum was collected from 24 patients (46% female, 22.1 ± 4.2 years old, 24.0 ± 2.6 kg/m2 body mass index [BMI]) preoperatively (6.4 ± 3.6 days post injury) and 6-months post-ACLR. T1ρ Magnetic Resonance Imaging (MRI) was collected for medial and lateral tibiofemoral articular cartilage at 12-months post-ACLR. A k-means cluster analysis was used to identify profiles based on biomarker changes over time and T1ρ relaxation times were compared between cluster groups controlling for sex, age, BMI, concomitant injury (either meniscal or chondral pathology), and Marx Score. RESULTS: One cluster exhibited increases in MCP-1 and COMP while the other demonstrated decreases in MCP-1 and COMP preoperatively to 6-months post-ACLR. The cluster group with increases in MCP-1 and COMP demonstrated greater lateral tibial (adjusted mean difference = 3.88, 95% confidence intervals [1.97-5.78]) and femoral (adjusted mean difference = 12.71, 95% confidence intervals [0.41-23.81]) T1ρ relaxation times. CONCLUSION: Profiles of increased serum levels of inflammation and matrix degradation markers preoperatively to 6-months post-ACLR are associated with MRI changes consistent with lesser lateral tibiofemoral cartilage proteoglycan density 12-months post-ACLR.

A Study on COMP and CTX-II as Molecular Markers for the Diagnosis of Intervertebral Disc Degeneration.

BACKGROUND: Diagnosis of intervertebral disc degeneration (IVDD) is challenging at the early stage. The cartilage oligomeric matrix protein (COMP) and extracellular matrix degradation products of C-telopeptide of type II collagen (CTX-II) serve as markers for the serological diagnosis of IVDD. Oxidative stress might cause IVDD and matrix degeneration. METHODS: A total of 128 male adult Sprague-Dawley (SD) rats were randomly and equally assigned to the experimental and control groups. The experimental group was used to construct IVDD models by acupuncture, while the control group underwent sham operation. The animals were executed every week for 8 weeks after intervertebral disc acupuncture, and serum samples were collected for the estimation of CTX-II and COMP concentrations by enzyme-linked immunosorbent assay (ELISA). Also, the histological changes and caudal magnetic resonance imaging (MRI) changes were examined in the intervertebral disc. RESULTS: IVDD in rats worsened with prolonged follow-up after acupuncture. At all the time points, the experimental group showed altered histological and caudal vertebra MRI signals, and serum CTX-II and COMP concentrations were significantly greater than those of the control group. These levels increase with the process of IVDD. CONCLUSION: Serum CTX-II and COMP estimation is a reliable method to diagnose IVDD, and their concentrations show a positive correlation with the process of IVDD.

Association between Markers of Synovial Inflammation, Matrix Turnover and Symptoms in Knee Osteoarthritis: A Cross-Sectional Study.

To investigate the association between markers of synovial inflammation and matrix turnover (MRI-based and serum biomarkers) and knee symptoms in established knee osteoarthritis (KOA). This cross-sectional study utilised data from a randomised, multicentre placebo-controlled trial (UK-VIDEO) of vitamin D therapy in symptomatic KOA. Data on serum biomarkers, type III collagen degradation (C3M), metabolite of C-reactive protein (CRPM) and cartilage oligomeric matrix protein (COMP), were available at baseline whilst contrast-enhanced (CE) MRI data were acquired in a subsample at baseline and annually. Knee symptoms were assessed using WOMAC at all visits. We examined the cross-sectional association between knee symptoms and three MRI-based and three serum markers of synovitis and matrix turnover, respectively. A total of 447 participants were included in the serum and 136 participants in the MRI analyses. MRI-defined medial perimeniscal synovitis was positively associated with knee pain and, suprapatellar and medial perimeniscal synovitis with knee function in multivariate analysis. We observed a statistically significant, negative association between a higher concentration of serum C3M and CRPM and knee pain, respectively. Furthermore, the highest CRPM quartile was negatively associated with knee function. Our findings suggest that, in established painful radiographic KOA, MRI-defined medial perimeniscal and suprapatellar synovitis were positively associated with knee symptoms. Serum-based C3M and CRPM markers were negatively associated with knee symptoms. Pain fluctuations are common in KOA and a better understanding of the relationship between markers of synovitis and matrix turnover and knee symptoms would facilitate a more accurate assessment of temporal changes in disease progression.

Cartilage oligomeric matrix protein as a marker of progressive liver fibrosis in biliary atresia.

This study aimed to determine whether mRNA and protein levels of cartilage oligomeric matrix protein (COMP), a glycoprotein responsible for modulating homeostasis of extracellular matrix, in the systemic and local liver environments were associated with clinical parameters of biliary atresia (BA) patients and might serve as a biomarker for BA severity. COMP protein levels in the circulation of 96 BA patients and 56 healthy controls and its mRNA and protein expressions in the liver of 20 BA patients and 5 non-BA patients were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry, respectively. In the circulation of BA patients, COMP levels were significantly higher than those in healthy controls. Compared with early-stage BA patients, those with advanced-stage including jaundice, fibrosis, and hepatic dysfunction had significantly increased circulating COMP levels. Raised circulating COMP levels were found to be independently correlated with degree of liver fibrosis. Survival analysis showed that elevated circulating COMP levels were significantly associated with decreased survival of BA patients. Receiver-operating characteristic curve analysis unveiled a diagnostic value of circulating COMP as a non-invasive biomarker of BA (AUC = 0.99), with a sensitivity of 100.0% and a specificity of 98.2%. In the liver, both COMP mRNA and protein expressions of BA patients with fibrosis were significantly greater than those of BA patients without fibrosis and non-BA patients. Collectively, increased circulating COMP might reflect unfavorable outcome of BA patients and have potential as a novel biomarker for the disease severity following Kasai-operation.

An exploratory study to investigate the association between age, physical activity, femoral trochlear cartilage thickness and biomarkers of tissue metabolism in adult males.

PURPOSE: To investigate the association between age, physical activity, femoral trochlear cartilage thickness and biomarkers of tissue metabolism in a cross-sectional sample of adult males. This study utilizes several emerging biomarkers that have been associated with early joint degenerative changes; serum COMP (cartilage oligomeric matrix protein), HA (hyaluronan) and lubricin. METHODS: Eighty-one males (age: mean (range): 43(18-70) years; body mass index: 25.2 (21.0-30.6) kg/m2) volunteered. Resting serum COMP, HA and lubricin concentrations were determined via commercially available enzyme-linked immunosorbent assay (ELISA) and femoral trochlear cartilage thickness via supra-patellar ultrasound imaging. Physical activity levels were assessed using questionnaires. Statistical analyses were performed using correlation and regression analyses. RESULTS: Age was correlated with lateral trochlear cartilage thickness (r = - 0.372; p < 0.01) and serum COMP (r = 0.342; p < 0.01). 7-day physical activity was correlated with serum COMP (r = 0.357, p < 0.01), and 12-month physical activity with both lateral trochlear cartilage thickness (r = 0.340, p = 0.01) and serum HA (r = 0.296, p < 0.05). Regression analyses revealed that age significantly accounted for the variability in lateral cartilage thickness and serum COMP, following the adjustment for potential cofounders. However, the association between age and lateral trochlear cartilage thickness was not moderated by physical activity levels (all p > 0.05). CONCLUSION: This study indicates that older age may be associated with thinner lateral trochlear cartilage and higher cartilage turnover. Being physically active may also be positive for lateral trochlear cartilage thickness. However, overall, both age and physical activity level only account for a small amount of the variability in cartilage thickness and serum biomarkers.

Longitudinal changes in tibial and femoral cartilage thickness are associated with baseline ambulatory kinetics and cartilage oligomeric matrix protein (COMP) measures in an asymptomatic aging population.

OBJECTIVE: To address the need for early knee osteoarthritis (OA) markers by testing if longitudinal cartilage thickness changes are associated with specific biomechanical and biological measures acquired at a baseline test in asymptomatic aging subjects. DESIGN: Thirty-eight asymptomatic subjects over age 45 years were studied at baseline and at an average of 7-9 year follow-up. Gait mechanics and knee MRI were measured at baseline and MRI was obtained at follow-up to assess cartilage thickness changes. A subset of the subjects (n = 12) also had serum cartilage oligomeric matrix protein measured at baseline in response to a mechanical stimulus (30-min walk) (mCOMP). Baseline measures, including the knee extension (KEM), flexion (KFM), adduction (KAM) moments and mCOMP, were tested for associations with cartilage thickness changes in specific regions of the knee. RESULTS: Cartilage change in the full medial femoral condyle (p = 0.005) and external medial femoral region (p = 0.041) was negatively associated with larger early stance peak KEM. Similarly, cartilage change in the full medial femoral region (p = 0.009) and medial femoral external region (p = 0.043) was negatively associated with larger first peak KAM, while cartilage change in the anterior medial tibia was positively associated with larger first peak KAM (p = 0.003). Cartilage change in the anterior medial tibia was also significantly associated (p = 0.011) with mCOMP levels 5.5-h post-activity (percentage of pre-activity levels). CONCLUSIONS: Interactions found between gait, mechanically-stimulated serum biomarkers, and cartilage thickness in an at-risk aging asymptomatic population suggest the opportunity for early detection of OA with new approaches that bridge across disciplines and scales.

COMP (Cartilage Oligomeric Matrix Protein) Neoepitope: A Novel Biomarker to Identify Symptomatic Carotid Stenosis.

OBJECTIVE: COMP (cartilage oligomeric matrix protein) is abundantly expressed in the cardiovascular system, cartilage, and atherosclerotic plaques. We investigated if the total COMP (COMPtotal) and COMP neoepitope (COMPneo) with other cardiovascular markers and clinical parameters could identify symptomatic carotid stenosis. Approach and Results: Blood samples were collected from patients with symptomatic carotid stenosis (stenosis, n=50), patients with stroke without carotid stenosis but small plaques (plaque, n=50), and control subjects (n=50). COMPtotal and COMPneo were measured using an ELISA. Ninety-two cardiovascular disease markers were measured by the Olink CVD kit. The presence of native COMP and COMPneo was determined by immunohistochemistry. The concentration of COMPneo was higher and COMPtotal was lower in the stenosis group. When the concentration was compared between the stenosis and control groups, IL-1ra (interleukin-1 receptor antagonist protein), IL6 (interleukin-6), REN (Renin), MMP1 (matrix metalloproteinase-1), TRAIL-R2 (tumor necrosis factor-related apoptosis-inducing ligand receptor 2), ITGB1BP2 (integrin beta 1 binding protein 2), and COMPneo were predictive of stenosis. Conversely, KLK6 (kallikrein-6), COMPtotal, NEMO (nuclear factor-kappa-B essential modulator), SRC (Proto-oncogene tyrosine-protein kinase Src), SIRT2 (SIR2-like protein), CD40 (cluster of differentiation 40), TF (tissue factor), MP (myoglobin), and RAGE (receptor for advanced glycation end-products) were predictive of the control group. Model reproducibility was good with the receiver operating characteristic plot area under the curve being 0.86. When comparing the plaque group and stenosis group, COMPneo, GAL (galanin), and PTX3 (pentraxin-related protein PTX3) were predictive of stenosis. Model reproducibility was excellent (receiver operating characteristic plot area under the curve 0.92). COMPneo was detected in smooth muscle-, endothelial-, and foam-cells in carotid stenosis. CONCLUSIONS: Degradation of COMP may be associated with atherosclerosis progression and generation of a specific COMP fragment-COMPneo. This may represent a novel biomarker that together with COMPtotal and other risk-markers could be used to identify symptomatic carotid stenosis. Graphic Abstract: A graphic abstract is available for this article.

Changes in knee adduction moment wearing a variable-stiffness shoe correlate with changes in pain and mechanically stimulated cartilage oligomeric matrix levels.

This study aimed to determine if changes in knee adduction moment (KAM) after 6 months of variable-stiffness shoe wear are associated with changes in symptoms or serum levels of cartilage oligomeric matrix protein (COMP) following a mechanical stimulus in subjects with medial knee osteoarthritis (OA). Twenty-five subjects were enrolled in the study and assigned a variable-stiffness shoe, and 19 subjects completed the 6-month follow-up. At baseline and follow-up subjects underwent gait analysis in control and variable-stiffness shoes, completed Western Ontario and McMaster Universities (WOMAC) questionnaires, and serum COMP concentrations were measured immediately before, 3.5 and 5.5 hours after a 30-minute walking activity. Relationships between changes in KAM (first peak and impulse) and changes in (a) COMP levels in response to the 30-minute walking activity and (b) WOMAC scores from baseline to 6-month follow-up were assessed by Pearson correlation coefficients. Changes in first peak KAM were associated with changes in COMP levels 5.5 hours postactivity from baseline to follow-up (R = .564, P = .045). Subjects with greater reductions in KAM had larger decreases in COMP (expressed as a percent of preactivity levels) at follow-up. Subjects with greater reductions in KAM impulse had significantly greater improvements in WOMAC Pain (R = -.56, P = .015) and Function (R = -.52, P = .028) scores at follow-up. The study results demonstrated the magnitude of reduction in the KAM wearing a variable-stiffness shoe is associated with decreases in mechanically stimulated COMP levels and pain/function. This work suggests that interactions between COMP and joint loading during walking should be further investigated in future studies of treatment outcomes in OA.

Multivariable logistic and linear regression models for identification of clinically useful biomarkers for osteoarthritis.

Osteoarthritis (OA) is the most common chronic degenerative joint disease which causes substantial joint pain, deformity and loss of activities of daily living. Currently, there are over 500 million OA cases worldwide, and there is an urgent need to identify biomarkers for early detection, and monitoring disease progression in patients without obvious radiographic damage to the joint. We have used regression modelling to describe the association of 19 of the currently available biomarkers (predictors) with key radiographic and clinical features of OA (outcomes) in one of the largest and best characterised OA cohort (NIH Osteoarthritis Initiative). We demonstrate that of the 19 currently available biomarkers only 4 (serum Coll2-1 NO2, CS846, COMP and urinary CTXII) were consistently associated with established radiographic and/or clinical features of OA. These biomarkers are independent of one another and provide additional predictive power over, and above established predictors of OA such as age, gender, BMI and race. We also show that that urinary CTXII had the strongest and consistent associations with clinical symptoms of OA as well as radiographic evidence of joint damage. Accordingly, urinary CTXII may aid in early diagnosis of OA in symptomatic patients without radiographic evidence of OA.

Locomotion replacement exercise cannot counteract cartilage biomarker response to 5 days of immobilization in healthy adults.

Biomarkers of cartilage metabolism are sensitive to changes in the biological and mechanical environment and can indicate early changes in cartilage homeostasis. The purpose of this study was to determine if a daily locomotion replacement program can serve as a countermeasure for changes in cartilage biomarker serum concentration caused by immobilization. Ten healthy male subjects (mean ± 1 standard deviation; age: 29.4 ± 5.9 years; body mass: 77.7 ± 4.1 kg) participated in the crossover 5-day bed rest study with three interventions: control (CON), standing (STA), and locomotion replacement training (LRT). Serum samples were taken before, during, and after bed rest. Biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. Cartilage oligomeric matrix protein (COMP) levels after 24 hours of bed rest decreased independently of the intervention (-16.8% to -9.8%) and continued to decrease until 72 hours of bed rest (minimum, -23.2% to -20.6%). LRT and STA did not affect COMP during bed rests (P = .056) but there was a strong tendency for a slower decrease with LRT (-9.4%) and STA (-11.7%) compared with CON (-16.8%). MMP-3 levels decreased within the first 24 hours of bed rest (CON: -22.3%; STA: -14.7%; LRT: -17%) without intervention effect. Both COMP and MMP-3 levels recovered to baseline levels during the 6-day recovery period. MMP-1, MMP-9, and TNF-α levels were not affected by immobilization or intervention. COMP and MMP-3 are mechano-sensitive cartilage biomarkers affected by immobilization, and simple interventions such as standing upright or LRT during bed rest cannot prevent these changes. Clinical significance: simple locomotion interventions cannot prevent cartilage biomarker change during bed rest.

The influence of a sustained 10-day hypoxic bed rest on cartilage biomarkers and subchondral bone in females: The FemHab study.

This study assessed the influence of a 10-day hypoxic bed rest on cartilage biomarkers and subchondral bone density across the patellofemoral joint (PFJ). Within clinical settings hypoxic tissue may arise in several types of disorders. Furthermore, a hypoxic environment is being considered for space flight habitats in the near future. Female participants (N = 12) participated in this study comprising three 10-day interventions: hypoxic ambulation (HAMB), normoxic bed rest (NBR), and hypoxic bed rest (HBR). Venous samples were collected prior to (day -2: Pre) and during the intervention (days 2 and 5), immediately before reambulation (D11) and 24 hr post intervention (R1). Blood samples were analyzed for: aggrecan, hyaluronan, Type IIA procollagen amino terminal propeptide (PIIANP), and cartilage oligomeric matrix protein (COMP). Total bone mineral density (BMD) in eight regions (2 mm × 10 mm) across the PFJ was determined. The three interventions (HAMB, HBR, and NBR) did not induce any significant changes in the cartilage biomarkers of hyaluronan or PIIANP. Aggrecan increased during the HAMB trial to 2.02 fold the Pre value. COMP decreased significantly in both NBR & HBR compared to HAMB on D5. There were significant differences in BMD measured across the PFJ from cortical patellar bone (735 to 800 mg/cm3 ) to femur trabecular (195 to 226 mg/cm3 ). However, there were no significant changes in BMD from Pre to Post bed rest. These results indicate that there were no significant detectable effects of inactivity/unloading on subchondral bone density. The biomarker of cartilage, COMP, decreased on D5, whereas the addition of hypoxia to bed rest had no effect, it appears that hypoxia in combination with ambulation counteracted this decrease.

[Biochemical predictors of cartilaginous tissue metabolic disorders for early osteoarthrosis evidence diagnostics.]

The complete laboratory and clinical instrumental examination was conducted, it included serum COMP test, circadian excretion of type II collagen C-terminal telopeptides Urine CartiLaps (СТХ II) and Т2 relaxometry in 29 patients of both sexes of the main group with early (0-I) X-ray osteoarthrosis stages, 30 subjects of comparison group with no X-ray osteoarthrosis evidences aged 44.7±5.9 years and 25 healthy subjects aged 26.3±2.6 years of the control group. The increase (р<0,05) of COMP and Urine CartiLaps levels as well as the increase of Т2 relaxation signal was found at early osteoarthrosis evidences. It was proven that there was (р<0.01) a connection (R=0.8) between COMP and Urine CTX II levels as well as (р<0.05) results of Т2 relaxometry (R=0.8). It was proven that collagen anisotropy and formation of chondromalacia areas as Т2 relaxometry showed in patients with early OA evidences were connected with accumulation of serum COMP and increase of type II collagen circadian renal excretion. The combination of laboratory and radiological methods of articular hyaline cartilage assessment may be used for finding early osteoarthrosis stages.

Impact of knee joint loading on fragmentation of serum cartilage oligomeric matrix protein.

The aim of the study was to examine the effect of mechanical knee joint loading on the fragmentation pattern of serum cartilage oligomeric matrix protein (COMP). Ten healthy men ran with knee orthoses that were passive or active (+30.9 N·m external flexion moments) on a treadmill (30 minute; v = 2.2 m/s). Lower-limb mechanics, serum COMP levels, and fragmentation patterns (baseline; 0, 0.5, 1, 2 hours postrunning) were analyzed. Running with active orthoses enhanced knee flexion moments, ankle dorsiflexion, and knee flexion angles (P < .05). There was an increase in serum COMP (+25%; pre: 8.9 ± 2.4 U/l; post: 10.7 ± 1.9 U/l, P = .001), COMP pentamer/tetramer (+88%; 1.88 ± 0.81, P = .007), trimer (+209%; 3.09 ± 2.65, P = .005), and monomer (+78%; 1.78 ± 0.85, P = .007) after running with passive orthoses and in serum COMP (+41%; pre: 8.5 ± 2.7 U/l; post: 11.3 ± 2.1 U/l, P < .001), COMP pentamer/tetramer (+57%; 1.57 ± 0.39, P = .007), trimer (+86%; 1.86 ± 0.47, P = .005), and monomer (+19%; 1.19 ± 0.34, P = .114) after running with active orthoses. Increased fragmentation might indicate COMP release from cartilage while running. Interestingly, 0.5 h up to 2 hours after running with passive orthoses, trimer (0.5 hour: 2.73 ± 3.40, P = .029; 2 hours: 2.33 ± 2.88, P = .037), and monomer (0.5 hour: 2.23 ± 2.33, P = .007; 1 hour: 2.55 ± 1.96, P = .012; 2 hours: 2.65 ± 2.50, P = .009) increased while after running with active orthoses, pentamer/tetramer (1 hour: 0.79 ± 0.28, P = .029), and trimer (1 hour: 0.63 ± 0.14, P = .005; 2 hours: 0.68 ± 0.34, P = .047) decreased. It seems that COMP degradation and clearance vary depending on joint loading characteristics.

Associations between suprapatellar pouch effusion-synovitis, serum cartilage oligomeric matrix protein, high sensitivity C-reaction protein, knee symptom, and joint structural changes in patients with knee osteoarthritis.

OBJECTIVES: To investigate the cross-sectional associations between suprapatellar pouch effusion-synovitis and serum levels of cartilage oligomeric matrix protein (COMP), high sensitivity C-reaction protein (hs-CRP), knee symptom, and structural changes in patients with symptomatic knee osteoarthritis (OA). METHOD: A total of 173 subjects were included. The osteophytes, joint space narrowing (JSN), and radiographic severity of OA were determined using X-ray. Cartilage defects, bone marrow lesions (BMLs), and suprapatellar pouch effusion-synovitis were assessed using magnetic resonance imaging. Serum levels of COMP and hs-CRP were measured by enzyme-linked immunosorbent assay. The knee joint symptom was self-reported using visual analogue scale. RESULTS: In this OA cohort, after adjustment for age, sex, and BMI, the presence of pathological effusion-synovitis was associated with serum levels of COMP (ß: 30.98, P = 0.018), and suprapatellar pouch effusion-synovitis maximum areas were associated with serum hs-CRP levels. Both suprapatellar pouch effusion-synovitis maximum area and grade were associated with osteophytes and Kellgren-Lawrence scores (ORs: 1.29-1.54, all P < 0.05). In patients with high tertile of hs-CRP, both suprapatellar pouch effusion-synovitis maximum area and grade were associated with cartilage defects at lateral and medial tibiofemoral sites (ORs: 3.01-8.41, all P < 0.05) after adjustment for covariates. In female patients, the significant associations were present between suprapatellar pouch effusion-synovitis and medial tibiofemoral BMLs (ORs: 1.43-1.53, all P < 0.05) after adjustment for covariates. CONCLUSIONS: Suprapatellar pouch effusion-synovitis was associated with serum levels of COMP as well as hs-CRP and knee structural abnormalities in patients with knee OA. These suggested that effusion-synovitis may play a role in knee OA.Key Points• Suprapatellar pouch effusion-synovitis is associated with serum levels of COMP in patients with knee OA.• Suprapatellar pouch effusion-synovitis is associated with cartilage defects in knee OA patients with high systemic inflammation.

Physical Activity Prevents Cartilage Degradation: A Metabolomics Study Pinpoints the Involvement of Vitamin B6.

Osteoarthritis (OA) is predominantly characterized by the progressive degradation of articular cartilage, the connective tissue produced by chondrocytes, due to an imbalance between anabolic and catabolic processes. In addition, physical activity (PA) is recognized as an important tool for counteracting OA. To evaluate PA effects on the chondrocyte lineage, we analyzed the expression of SOX9, COL2A1, and COMP in circulating progenitor cells following a half marathon (HM) performance. Therefore, we studied in-depth the involvement of metabolites affecting chondrocyte lineage, and we compared the metabolomic profile associated with PA by analyzing runners' sera before and after HM performance. Interestingly, this study highlighted that metabolites involved in vitamin B6 salvage, such as pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate, were highly modulated. To evaluate the effects of vitamin B6 in cartilage cells, we treated differentiated mesenchymal stem cells and the SW1353 chondrosarcoma cell line with vitamin B6 in the presence of IL1ß, the inflammatory cytokine involved in OA. Our study describes, for the first time, the modulation of the vitamin B6 salvage pathway following PA and suggests a protective role of PA in OA through modulation of this pathway.

Identifying the role of ASPN and COMP genes in knee osteoarthritis development.

BACKGROUND: Osteoarthritis (OA) is a common cause of musculoskeletal disability among elders and is characterized by late-onset degeneration of articular cartilage. OA affects various joints, commonly hand, knee, and hip, with clinical features that are unique to each joint. This study was initiated to identify and evaluate the role of the ASPN and COMP genes in the development of knee OA. METHODS: A case-control study was carried out involving 500 cases with knee OA (diagnosed by the American College of Rheumatology) and an equal number of healthy controls. Blood was drawn for genomic DNA isolation. PCR-RFLP and TaqMan assay methods were used to identify the SNPs. mRNA and protein expression of genes were carried out in peripheral blood lymphocytes (PBLs) by RT-PCR and Western immunoblotting. The data obtained were analyzed for the statistical significance between control and case groups. RESULTS: The variant genotype of ASPN and COMP genes was found to be present at a relatively higher frequency in cases than controls. RT-PCR and immunochemical studies revealed increased mRNA and protein expression of such gene in PBLs isolated from cases of knee OA as compared to healthy control. CONCLUSION: The allelic alteration in ASPN and COMP genes in knee OA cases points to the role of these genes in the development of knee OA. Further, increased mRNA and protein expression of ASPN and COMP in peripheral blood samples of patients with the disease suggest that expression profile of candidate gene could be used as a biomarker for predicting the development and progression of knee OA.

Combined use of Serum miR-338-3p, Cartilage Oligomeric Matrix Protein and Chondroitin Sulfate-846 in the Early Diagnosis of Knee Osteoarthritis.

BACKGROUND: In this study, the serum levels of miR-338-3p, COMP, and CS-846 were detected in the patients with KOA and healthy controls, to explore the value of miR-338-3p, COMP, and CS-846 in the early diagnosis of KOA. METHODS: Real-time PCR was carried out to evaluate the level of miR-338-3p in KOA patients and healthy controls. Spearman's correlation coefficient was performed to examine the correlation between the expression of miR-338-3p, COMP, and CS-846. Receiver operating characteristic (ROC) curves were carried out to evaluate the diagnostic values of miR-338-3p, COMP, and CS-846 for KOA patients. RESULTS: In the current study, we first demonstrated that serum miR-338-3p, COMP, and CS-846 levels were increased in KOA patients compared to healthy controls. Moreover, the increase of miR-338-3p, COMP, and CS-846 levels positively correlated with VAS scores and joint space narrowing, suggesting miR-338-3p positively correlated with comprehensive disease severity. In addition, miR-338-3p, COMP, and CS-846 could be used as an independent biomarker for KOA patients. More importantly, combined use of miR-338-3p, COMP, and CS-846 demonstrates a higher diagnostic value with an AUC 0.926 for KOA patients. CONCLUSIONS: The combination of miR-338-3p, COMP, and CS-846 demonstrated higher diagnostic value for KOA patients, indicating their combination as novel and promising biomarkers for diagnosis and disease severity of KOA.

Serum-based soluble markers differentiate psoriatic arthritis from osteoarthritis.

OBJECTIVES: We aimed to identify soluble biomarkers that differentiate psoriatic arthritis (PsA) from osteoarthritis (OA). METHODS: Markers of cartilage metabolism (cartilage oligomeric matrix protein [COMP], hyaluronan), metabolic syndrome (adiponectin, adipsin, resistin, hepatocyte growth factor [HGF], insulin, leptin) and inflammation (C-reactive protein [CRP], interleukin-1ß [IL-1ß], IL-6, IL-8, tumour necrosis factor alpha [TNFα], monocyte chemoattractant protein-1 [MCP-1], nerve growth factor [NGF]) were compared in serum samples from 201 patients with OA, 77 patients with PsA and 76 controls. Levels across the groups were compared using the Kruskal-Wallis test. Pairwise comparisons were made with Wilcoxon rank-sum test. Multivariate logistic regression analyses were performed to identify markers that differentiate PsA from OA. Receiver operating characteristic (ROC) curves were constructed based on multivariate models. The final model was further validated in an independent set of 73 PsA and 75 OA samples using predicted probabilities calculated with coefficients of age, sex and biomarkers. RESULTS: Levels of the following markers were significantly different across the three groups (p<0.001)-COMP, hyaluronan, resistin, HGF, insulin, leptin, CRP, IL-6, IL-8, TNFα, MCP-1, NGF. In multivariate analysis, COMP (OR 1.24, 95% CI 1.06 to 1.46), resistin (OR 1.26, 95% CI 1.07 to 1.48), MCP-1 (OR 1.10, 95% CI 0.07 to 1.48) and NGF (OR<0.001, 95% CI <0.001 to 0.25) were found to be independently associated with PsA versus OA. The area under the ROC curve (AUROC) for this model was 0.99 compared with model with only age and sex (AUROC 0.87, p<0.001). Similar results were obtained using the validation sample. CONCLUSION: A panel of four biomarkers may distinguish PsA from OA. These results need further validation in prospective studies.