Changes In Cartilage Oligomeric Matrix Protein Research Articles

COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways

BackgroundPancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. MethodsELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. ResultsELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-β1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. ConclusionIn conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

In vitro and in silico analysis of a E559K mutation on cartilage oligomeric matrix protein

Pseudoachondroplasia (PSACH) is known as an autosomal dominant disorder associated with mutations in the gene of cartilage oligomeric matrix protein (COMP). The pathomolecular mechanisms of PSACH as a result of C-terminal globular region (CTD) mutations remain unclear. A heterozygous mutation (E559 K) in a Chinese family diagnosed with PSACH was reported in this study. To understand the pathogenesis of this mutation, we studied chondrogenic differentiation of patient menstrual blood-derived stem cells (MenSCs), and the impact of the mutation on structural changes of COMP was investigated using all-atom molecular dynamics simulation. The results suggested that the interactions with calcium and other molecules in the mutant structure were affected resulting in misfolding of the protein, which leads to ER stress and finally affects the survival of chondrocytes. The findings may promote the understanding of the pathomolecular mechanisms of PSACH, and possibly the development of drugs to treat the disease.

Cartilage oligomeric matrix protein responses to a mechanical stimulus associate with ambulatory loading in individuals with anterior cruciate ligament reconstruction.

Mechanical factors have been implicated in the development of osteoarthritis after anterior cruciate ligament (ACL) reconstruction. This study tested for associations between ambulatory joint loading (total joint moment [TJM] and vertical ground reaction force [vGRF]) and changes in serum levels of cartilage oligomeric matrix protein (COMP) in response to a mechanical stimulus (30-min walk) in individuals with ACL reconstruction. Twenty-five subjects (mean age: 34.5 ± 9.8 years; 2.2 ± 0.2 years post-surgery) with primary unilateral ACL reconstruction underwent gait analysis for assessment of peak vGRF and TJM first (TJM1) and second (TJM2) peaks. Serum COMP concentrations were measured by enzyme-linked immunosorbent assay immediately before, 3.5 h, and 5.5 h after a 30-min walk. Pearson correlation coefficients and backward stepwise multiple linear regression analysis, with adjustments for age, sex, body mass index, and between-limb speed difference, assessed associations between changes in COMP and between-limb differences in joint loading parameters. Greater TJM1 (R = 0.542, p = 0.005), TJM2 (R = 0.460, p = 0.021), and vGRF (R = 0.577, p = 0.003) in the ACL-reconstructed limb as compared to the contralateral limb were associated with higher COMP values 3.5 h following the 30-min walk. Change in COMP at 5.5 h became a significant predictor of the between-limb difference in TJM1 and vGRF in multivariate analyses after accounting for the between-limb speed difference. These results demonstrate that higher TJM and vGRF in the ACLR limb as compared to the contralateral limb are associated with higher relative COMP levels 3.5 and 5.5 h after a 30-min walk. Future work should investigate the effect of therapies to alter joint loading on the biological response in individuals after ACL reconstruction.

Study of serum traditional and nontraditional biomarkers in Rheumatoid arthritis patients

The study of biomarkers in Rheumatoid arthritis (RA) is highly indispensable to understand mechanisms of pathogenesis, diagnosis, prognosis, and treatment of disease. The role of traditional biomarkers like Anti-CCP, RF, and inflammatory markers like ESR and CRP is well established. In this study, we aimed to measure nontraditional biomarkers like Hyaluronic acid (HA), Cartilage oligomeric matrix protein (COMP), and Osteocalcin in the serum of RA patients and also to establish an association with traditional markers. It was a cross-sectional study involving 152 RA patients based on the 1987 ACR criteria for the diagnosis of RA and 68 age‑ and sex-matched healthy controls. After the clinical examination, traditional markers were assessed to measure the disease activity along with non traditional markers in RA patients. All the values were expressed as median (25th–75th percentile). In our study, there was a significant increase in serum HA levels in RA patients compared to healthy controls (p < 0.03), whereas no significant difference in serum COMP and osteocalcin levels. The traditional inflammatory markers were significantly increased in RA patients than controls with (p < 0.001). The serum HA levels were significantly correlated with traditional markers in RA patients. Conclusion: Significant increase in serum HA level in RA patients indicating synovial inflammation, but there were no notable changes in COMP and osteocalcin level in serum presuming the combination of these markers may be useful along with traditional markers in the different stages of RA.

Label-Free and Direct Visualization of Multivalent Binding of Bone Morphogenetic Protein-2 with Cartilage Oligomeric Matrix Protein.

This work presents the first direct evidence of multivalent binding between bone morphogenetic protein-2 (BMP-2) and cartilage oligomeric matrix protein (COMP) using high-resolution atomic force microscopy (AFM) imaging. AFM topographic images reveal the molecular morphology of COMP, a pentameric protein whose five identical monomer units bundle together at N-termini, extending out with flexible chains to C-termini. Upon addition of BMP-2, COMP molecules undergo conformational changes at the C-termini to enable binding with BMP-2 molecules. AFM enables local structural changes of COMP to be revealed upon binding various numbers, 1-5, of BMP-2 molecules. These BMP-2/COMP complexes exhibit very different morphologies from those of COMP: much more compact and thus less flexible. These molecular-level insights deepen current understanding of the mechanism of how the BMP-2/COMP complex enhances osteogenesis among osteoprogenitor cells, i.e., multivalent presentation of BMP-2 via the stable and relatively rigid BMP-2/COMP complex could form a lattice of interaction between multiple BMP-2 and BMP-2 receptors. These ligand-receptor clusters lead to fast initiation and sustained activation of the Smad signaling pathway, resulting in enhanced osteogenesis. This work is also of translational importance as the outcome may enable use of lower BMP-2 dosage for bone repair and regeneration.

Combined detection of COMP and CS846 biomarkers in experimental rat osteoarthritis: a potential approach for assessment and diagnosis of osteoarthritis

BackgroundTo comprehensively evaluate the diagnostic value of serum cartilage oligomeric matrix protein (COMP) and chondroitin sulfate 846 epitope (CS846) biomarkers in osteoarthritis (OA), longitudinal and combined measurement of serum COMP and CS846 were performed at different stages in the pathological process of OA in a rat model of anterior cruciate ligament transection (ACLT).MethodsSixty male Sprague-Dawley rats were randomly divided into two groups, including a model group (n = 30) and a control group (n = 30). Rat models were established by ACLT surgery, and sham operations were performed on rats in the control group. Prior to surgery and at 2, 4, 6, 8, and 10 weeks after ACLT surgery, serum levels of COMP and CS846 biomarkers were determined using an enzyme-linked immunosorbent assay approach. Five rats per group were euthanized at 2, 4, 6, 8, and 10 weeks after surgery, after which tibial plateau specimens were collected. Macroscopic observation and histological examination were employed for rat tibial plateau. Histological changes in articular cartilage were evaluated according to Osteoarthritis Research Society International (OARSI) scoring criteria. The area under the curve (AUC) of COMP, CS846, and combined biomarkers was compared using receiver operating characteristic (ROC) curve.ResultsWithin 10 weeks after surgery, serum levels of COMP and CS846 in the model group were significantly higher when compared to those in the control group. Moreover, a significant correlation was observed between changes in COMP and CS846 levels. At each time point, macroscopic observations and OARSI scores were significantly increased in the development of OA. The AUC of combined biomarkers was higher compared to that of COMP and CS846 alone. Finally, a positive relationship was found between levels of COMP and CS846 and the OARSI score.ConclusionsIn this study, we found that combined detection of serum CS846 and COMP levels can be used for diagnosis and monitoring of OA progression.

Changes in Cartilage Biomarker Levels During a Transcontinental Multistage Footrace Over 4486 km

Background: Cartilage turnover and load-induced tissue changes are frequently assessed by quantifying concentrations of cartilage biomarkers in serum. To date, information on the effects of ultramarathon running on articular cartilage is scarce. Hypothesis: Serum concentrations of cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP)–1, MMP-3, MMP-9, COL2-3/4C long mono (C2C), procollagen type II C-terminal propeptide (CPII), and C2C:CPII will increase throughout a multistage ultramarathon. Study Design: Descriptive laboratory study. Methods: Blood samples were collected from 36 runners (4 female; mean age, 49.0 ± 10.7 years; mean body mass index, 23.1 ± 2.3 kg/m2 [start] and 21.4 ± 1.9 kg/m2 [finish]) before (t0) and during (t1: 1002 km; t2: 2132 km; t3: 3234 km; t4: 4039 km) a 4486-km multistage ultramarathon. Serum COMP, MMP-1, MMP-3, MMP-9, C2C, and CPII levels were assessed using commercial enzyme-linked immunosorbent assays. Linear mixed models were used to detect significant changes in serum biomarker levels over time with the time-varying covariates of body weight, running speed, and daily running time. Results: Serum concentrations of COMP, MMP-9, and MMP-3 changed significantly throughout the multistage ultramarathon. On average, concentrations increased during the first measurement interval (MI1: t1-t0) by 22.5% for COMP (95% CI, 0.29-0.71 ng/mL), 22.3% for MMP-3 (95% CI, 0.24-15.37 ng/mL), and 95.6% for MMP-9 (95% CI, 81.7-414.5 ng/mL) and remained stable throughout MI2, MI3, and MI4. Serum concentrations of MMP-1, C2C, CPII, and C2C:CPII did not change significantly throughout the multistage ultramarathon. Changes in MMP-3 were statistically associated with changes in COMP throughout the ultramarathon race (MMP-3: Wald Z = 3.476, P = .001). Conclusion: Elevated COMP levels indicate increased COMP turnover in response to extreme running, and the association between load-induced changes in MMP-3 and changes in COMP suggests the possibility that MMP-3 may be involved in the degradation of COMP. Clinical Relevance: These results suggest that articular cartilage is able to adapt even to extreme physical activity, possibly explaining why the risk of degenerative joint disease is not elevated in the running population.

Clinical and biochemical study of the comparative efficacy of topical versus oral glucosamine/chondroitin sulfate on osteoarthritis of the knee

Aim of the workThe aim of this study was to detect and compare the efficacy of topical and oral glucosamine/chondroitin sulfate on knee OA (OAK), and to prove their efficacy on sparing the articular cartilage among the Egyptian patients. Patients and methods180 patients with OAK were included and randomly divided into 2 groups, each of 90 patients. One group took 1500mg oral glucosamine/chondroitin sulfate and the other group used topical glucosamine/chondroitin sulfate for 3months. The diagnosis was based on the American College of Rheumatology (ACR) criteria for OAK. Age, duration of OA, and body mass index (BMI) of the patients were recorded. Knee radiographs were assessed with the Kellgren–Lawrence scale. The severity of knee pain, stiffness, and disability were measured using the visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The serum C-reactive protein (CRP) and Cartilage oligomeric matrix protein changes (COMP) were measured. ResultsNo statistical difference was found between the 2 groups regarding age, sex, duration of OA, and Kellgren–Lawrence grading scale. Both VAS and WOMAC subscores showed significant equal relief of pain and joint function between the 2 groups regardless of the severity or duration of knee OA. Topical glucosamine was superior to the oral route in improving stiffness and function. ConclusionTopical and oral glucosamine/chondroitin sulfate are safe and equally effective on improving knee pain, stiffness and function. Glucosamine/chondroitin sulfate is beneficial as a symptomatic treatment and not as a cartilage sparing drug in the treatment of OAK.

Deformational behaviour of knee cartilage and changes in serum cartilage oligomeric matrix protein (COMP) after running and drop landing

To investigate (1) the effect of running and drop landing interventions on knee cartilage deformation and serum cartilage oligomeric matrix protein (COMP) concentration and (2) if the changes in cartilage volume correlate with the changes in serum COMP level. Knee joint cartilage volume and thickness were determined using magnetic resonance imaging (MRI) as well as COMP concentration from serum samples before and after in vivo loading of 14 healthy adults (seven male and seven female). Participants performed different loading interventions of 30 min duration on three different days: (1) 100 vertical drop landings from a 73 cm high platform, (2) running at a velocity of 2.2m/s (3.96 km), and (3) resting on a chair. Blood samples were taken immediately before, immediately after and 0.5h, 1h, 2h and 3h post intervention. Pre- and post-loading coronal and axial gradient echo MR images with fat suppression were used to determine the patellar, tibial and femoral cartilage deformation. Serum COMP levels increased immediately after the running (+30.7%, pre: 7.3U/l, 95% confidence interval (CI): 5.6, 8.9, post: 9.1U/l, 95% CI: 7.2, 11.0, P=0.001) and after drop landing intervention (+32.3%, pre: 6.8U/l, 95% CI: 5.3, 8.4; post: 8.9U/l, 95% CI: 6.8, 10.9, P=0.001). Cartilage deformation was more pronounced after running compared to drop landing intervention, with being significant (volume: P=0.002 and thickness: P=0.001) only in the lateral tibia. We found a significant correlation (r(2)=0.599, P=0.001) between changes in serum COMP (%) and in cartilage volume (%) after the drop landing intervention, but not after running. In vivo exercise interventions differentially regulate serum COMP concentrations and knee cartilage deformations. The relation between changes in COMP and in cartilage volume seems to depend on both mechanical and biochemical factors.

COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker

Objective:Cartilage oligomeric matrix protein (COMP), primarily found in cartilage, is thought to be an important regulator of assembly and maintenance of the fibrillar collagen I and II networks. Recently, COMP...

Change in serum measurements of cartilage oligomeric matrix protein and association with the development and worsening of radiographic hip osteoarthritis

To determine the association between changes in serum levels of cartilage oligomeric matrix protein (COMP) and serum N-telopeptide crosslinks (NTX) over a 6-year interval with the development and progression of radiographically apparent hip osteoarthritis (RHOA) in a community sample of elderly women over 8.3 years of follow-up. Pelvic radiographs were obtained a mean of 8.3 years apart in Caucasian women > or =65 years of age enrolled in the Study of Osteoporotic Fractures. From a cohort of 5928 subjects, we randomly sampled study subjects ( approximately 170 per group) to perform two nested case-control studies, one of RHOA incidence and the other of RHOA progression. Baseline and year 6 serum COMP and serum NTX levels were measured by enzyme linked immunosorbent assay in duplicate and percentage change in serum levels was calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) for 1 standard deviation (SD) change in the serum COMP and NTX level differences were calculated using logistic regression analysis and used to predict the development or progression of RHOA, adjusting for potential covariates. The percentage change in the level of serum COMP from baseline to year 6 was found to be a risk factor for the development of incident RHOA [adjusted OR of 1.58 per 1 SD increase (95% CI: 1.19-2.09)], and reduction of progression of RHOA [adjusted OR of 0.74 per 1 SD increase (95% CI: 0.58-0.96)]. Quartile analysis of serum COMP changes revealed that the three highest quartiles of change in serum COMP were associated with (1) a five-fold greater risk of developing incident RHOA [adjusted OR=5.42 (95% CI: 2.80-10.60)], and (2) a 50% decreased risk of developing progression of RHOA [adjusted OR=0.48 (95% CI: 0.30-0.80)]. No significant association was found between changes in serum NTX levels from baseline to year 6 with either incident RHOA or the progression of existing RHOA. Measurement of serum COMP at two distinct timepoints may be a method of identifying patients at risk for developing incident RHOA and those with baseline RHOA that will not rapidly progress.

Relationship between serum cartilage oligomeric matrix protein levels and disease progression in osteoarthritis of the knee joint.

The value of serum cartilage oligomeric matrix protein (COMP) as a marker of disease progression was investigated in 81 hospital out-patients with clinical knee osteoarthritis (OA). Progressing patients were defined by a decrease of > or = 2 mm in joint space on X-ray or requiring knee surgery during the 5 yr of follow-up. Of the 57 patients for whom full data were available, 20 progressed and 37 did not progress. Serum COMP levels increased during the first year in those who progressed (mean 6.42 micrograms/ml) (S.D. 6.64) compared to those who did not progress [mean 0.07 microgram/ml (S.D. 4.99); P < 0.001]. Changes in COMP during the first year were related to baseline COMP (r = -0.672, P < 0.001) and weight-to-height ratio (r = 0.272, P = 0.47). After allowing for these variables, serum COMP increased during the first year in progressive patients by 5.04 micrograms/ml [95% confidence interval (CI): (2.61, 7.46)] more than in non-progressive patients. Discriminant analysis gave a sensitivity of 70% and specificity of 78% at a cut-off value of 3.17 micrograms/ml. Baseline serum COMP levels did not differ between the groups but were related to late phase scintigraphy scan abnormalities. These observations suggest that the changes in serum COMP may have prognostic significance and are consistent with a model of OA in which early signs of episodic clinical progression can be found in the cartilage as well as in subchondral bone.