Potential Biomarkers Of Osteoarthritis Research Articles

Biomarkers of Hand Osteoarthritis Are Detectable after Mechanical Exercise.

Background: Hand osteoarthritis (OA) is one of the most common joint diseases, but studies on biomarkers are rare. The aim of this explorative study was (a) to evaluate potential biomarkers of hand OA, (b) to identify an optimal time point to sample venous blood, and (c) to correlate biomarker levels with radiological and clinical scores. Methods: Four female cohorts were investigated. One with a more Heberden-accentuated OA and one with a more Bouchard-accentuated hand OA, and two symptom-free control groups aged 20–30 or 50–75 years. The venous blood was sampled before and at eight time points after mechanical exercise of the OA hand. X-rays of OA hands were assessed using the Kellgren and Lawrence as well as Kallman scores. Participants were evaluated clinically using the AUSCAN™ Index, visual analog scale (VAS), and Health Assessment Questionnaire (HAQ). Serum levels of seven biomarkers were measured by ELISA. Results. The concentrations of CPII, COMP, IL-15, sVCAM-1, NGAL, and PIIANP were significantly increased within 15 min after exercise. PIIANP was markedly elevated in the Heberden-accentuated OA group as compared to both control groups, but did not correlate with any radiological or clinical score. Analysis of the probabilistic index further revealed that CPII can distinguish between Bouchard’s OA and premenopausal controls whereas COMP can discriminate between Bouchard’s and Heberden’s OA. Conclusions: This study demonstrates that even previously undetectable biomarkers can be quantified in serum after mechanical exercise. Future larger studies are needed to determine specificity and sensitivity of these markers and their ability to diagnose even pre-radiological OA.

Analysis of methylation datasets identified significantly changed genes and functional pathways in osteoarthritis.

Researches indicate that epigenetics was involved in osteoarthritis (OA). The purpose of this study was to describe the alterations of DNA methylation in hip and knee OA by comparing DNA methylome of OA cartilage and non-OA samples and to identify novel genes and pathways associated with OA. We gained two expression profiling datasets (GSE73626 and GSE63695) from the GEO dataset. The RnBeads in R package was used to identify differentially methylated CpG sites. Genes that showed significant differences in DNA methylation between OA and normal control groups underwent functional annotation analysis using the online tool of GeneCodis. Furthermore, we used the Sequenom MassARRAY platform (CapitalBio, Beijing, China) to perform the quantitative methylation analysis. A total of 249 hypermethylated sites and 96 hypomethylated sites were obtained from OA samples compared with normal control samples. Functional analysis of differentially methylated genes obtained that embryonic skeletal system morphogenesis, cartilage development, and skeletal system development may be involved in the pathogenesis of OA. Eight genes including HOXB3, HOXB4, HOXB6, HOXC4, HOXC10, HOXD3, TBX3, and TBX5 were identified as potential novel biomarkers for OA. Taken together, our study found different molecular characteristics between OA patients and normal controls. This may provide new clues to elucidate the pathogenesis of OA.Key Points• Embryonic skeletal system morphogenesis, cartilage development, skeletal system development may be involved in the pathogenesis of OA.• Eight genes are identified as potential novel markers for OA.• Our future in vivo molecular intervention experiments will extend our current findings.

Vascular cell adhesion molecule1 in patients with severe osteoarthritis of the hip : Aprospective cross-sectional study.

SummaryBackgroundOsteoarthritis (OA) of the hip is a frequent and debilitating joint disease. Only few clinical risk factors for hip OA are established and clinically applicable biomarkers to identify patients at risk are still lacking. The glycoprotein vascular cell adhesion molecule 1 (VCAM-1) is expressed by chondrocytes and synovial tissue and was a predictive marker for development of severe large joint OA in a previous study.ObjectiveIt was tested whether increased serum levels of VCAM-1 are prevalent in patients with severe OA of the hips.MethodsIn this prospective, multicenter, cross-sectional study, risk factors of severe hip OA were investigated in patients scheduled for hip joint arthroplasty and 100 patients were randomly selected for validation of VCAM-1 as a potential biomarker for hip OA. Serum samples were analyzed by an enzyme-linked immunosorbent assay and compared with a sex and age-matched control cohort.ResultsThe groups were similar in age, gender ratio and prevalence of diabetes. Serum concentrations of VCAM-1 were 8% higher in OA patients compared to controls, without reaching statistical significance (818 ng ml−1, 95% confidence interval, CI 746–891 ng ml−1 versus 759 ng m−1, 95% CI 711–807 ng ml−1; P = 0.4839).ConclusionThe results of this study show that serum concentrations of VCAM-1 cannot distinguish patients with severe hip OA from age and sex-matched controls.

MicroRNA-15a-5p Regulates the Development of Osteoarthritis by Targeting PTHrP in Chondrocytes.

Background and Aims A growing body of research has demonstrated that the degeneration of chondrocytes is the primary cause of osteoarthritis (OA). Parathyroid hormone-related protein (PTHrP) can alleviate the degeneration of chondrocytes via promotion of chondrocyte proliferation and inhibition of terminal differentiation, but the underlying mechanism remains unknown. This study aimed to identify the microRNAs (miRNAs) that may target PTHrP and regulate the proliferation and terminal differentiation of chondrocytes. Methods Bioinformatic analysis was used to predict which miRNAs target PTHrP. We collected human knee cartilage specimens to acquire the primary chondrocytes, which we then used to test the expression and function of the targeted miRNAs. To explore the effects of miR-15a-5p on the putative binding sites, specific mimics or inhibitors were transfected into the chondrocytes. Furthermore, a dual-luciferase reporter gene assay and chondrocyte degeneration-related factors were used to verify the possible mechanism. Results The expression of PTHrP was upregulated in the OA chondrocytes, whilst miR-15a-5p was downregulated in the OA chondrocytes. A negative correlation was observed between PTHrP and miR-15a-5p. The knockdown of miR-15a-5p promoted the growth of chondrocytes and inhibited calcium deposition, whilst overexpression of miR-15a-5p reversed this trend. The effect of miR-15a-5p overexpression was neutralised by PTHrP. Dual-luciferase reporter assays revealed that PTHrP can be used as a novel targeting molecule for miR-15a-5p. Conclusions miR-15a-5p promotes the degeneration of chondrocytes by targeting PTHrP and, in addition to helping us understand the development of OA, may be a potential biomarker of OA.

MiRNA-146a-5p is upregulated in serum and cartilage samples of patients with osteoarthritis.

Osteoarthritis (OA) is a widely prevalent joint disease leading to motor disability and pain. Appropriate indicators for identifying patients at risk for this progressive disease, identifying molecular events for detecting early phases of the disease, or biomarkers to screen for treatment responses, however, are lacking. Micro RNAs (miRNAs), which play crucial roles in OA, could be potential biomarkers of OA. Because circulating miRNA levels reflect the disease state, they may be useful for OA screening and as diagnostic tools, reducing the need for invasive procedures and minimizing the cost of current diagnostic methods. The expression levels of 18 microRNAs (let-7e-5p, miR-21-5p, miR-93-5p, miR-101-3p, miR-103a-3p, miR-130a-3p miR-146a-5p, miR-16-5p, miR-193b-3p miR-199a-3p, miR-210-3p, miR-222-3p, miR-22-3p, miR-27a-3p, miR-27b-3p, miR-335-5p, miR-454-3p, and miR-98-5p) were analyzed by quantitative real-time polymerase chain reaction in the cartilage tissues and serum samples of 28 OA patients and were compared to those of 2 healthy controls. Expression of microRNA-146a-5p was significantly upregulated in the cartilage (p=0.006) and serum (p=0.002) of OA patients. The expression levels of miR-146a-5p in the serum were positively correlated with those in the cartilage (Pearson correlation coefficient R=0.32; p=0.002). miR-146a-5p was significantly overexpressed in patients with OA, both in the articular cartilage tissue and serum, with a positive correlation between the levels in both types of samples. Therefore, the miR-146a-5p serum level could reflect the molecular processes in the cartilage, suggesting its clinical utility as a biomarker for OA management. Implementing noninvasive biomarker using serum miRNAs involves the analysis of the misregulated miRNAs linked to the cartilage pathology.

Clinical Diagnosis Value of miR-29b-3p in Peripheral Blood Mononuclear Cells and Synovial Fluid Among Osteoarthritis Patients.

The current study aims to verify the abnormal expression of miR-29b-3p in peripheral blood mono-nuclear cells and synovial fluid of patients with osteoarthritis (OA), and to explore whether this abnormality is related to the severity of OA. The level of miR-29b-3p was detected by real-time quantitative PCR in peripheral blood mononuclear cells (PBMCs) and joint fluid. Kellgren-Lawrence X-ray grading was performed in patients with OA, and the correlation between miR-29b-3p and age, weight and Kellgren-Lawrence X-ray grading was analyzed. The expression of miR-29b-3p in PBMCs of patients with OA was higher than that of the healthy control group ((4.48 ± 2.44) vs. (7.40 ± 4.10), p < 0.05), and the difference was statistically significant. In the synovial fluid of OA patients, the expression of miR-29b-3p was higher than that of the non-OA group ((4.90 ± 2.33) vs. (77.55 ± 2.79), p < 0.05), and the difference was statistically significant. Meanwhile, the relative expression of miR-29b-3p in PBMCs of patients with OA was positively correlated with age, body mass index (BMI), Kellgren-Lawrence X-ray classification (r = 0.896, p < 0.001; r = 0.880, p < 0.001; r = 0.357, p = 0.005). The high expression of miR-29b-3p in PBMCs and synovial fluid of patients with OA was positively correlated with age, body mass index and Kellgren-Lawrence X-ray classification. Therefore, miR-29b-3p may be involved in the pathogenesis of OA, and miR-29b-3p may be used as a potential biomarker for OA.

Application of global metabolomic profiling of synovial fluid for osteoarthritis biomarkers

Osteoarthritis affects over 250 million individuals worldwide. Currently, there are no options for early diagnosis of osteoarthritis, demonstrating the need for biomarker discovery. To find biomarkers of osteoarthritis in human synovial fluid, we used high performance liquid-chromatography mass spectrometry for global metabolomic profiling. Metabolites were extracted from human osteoarthritic (n = 5), rheumatoid arthritic (n = 3), and healthy (n = 5) synovial fluid, and a total of 1233 metabolites were detected. Principal components analysis clearly distinguished the metabolomic profiles of diseased from healthy synovial fluid. Synovial fluid from rheumatoid arthritis patients contained expected metabolites consistent with the inflammatory nature of the disease. Similarly, unsupervised clustering analysis found that each disease state was associated with distinct metabolomic profiles and clusters of co-regulated metabolites. For osteoarthritis, co-regulated metabolites that were upregulated compared to healthy synovial fluid mapped to known disease processes including chondroitin sulfate degradation, arginine and proline metabolism, and nitric oxide metabolism. We utilized receiver operating characteristic analysis to determine the diagnostic value of each metabolite and identified 35 metabolites as potential biomarkers of osteoarthritis, with an area under the receiver operating characteristic curve >0.9. These metabolites included phosphatidylcholine, lysophosphatidylcholine, ceramides, myristate derivatives, and carnitine derivatives. This pilot study provides strong justification for a larger cohort-based study of human osteoarthritic synovial fluid using global metabolomics. The significance of these data is the demonstration that metabolomic profiling of synovial fluid can identify relevant biomarkers of joint disease.

Study on the clinical value of miRNA98b as a potential biomarker for osteoarthritis

Objective: Osteoarthritis is a serious threat to the health of patients. Biomarkers have important significance in the diagnosis of bone arthritis. Bone mineral density is one of the important indicators for the detection of bone joint inflammation, but its detection is time-consuming and laborious. MicroRNA regulates cancer and inflammation. This study was to investigate the potential value of biomarkers miRNA98b in the diagnosis of early osteoarthritis. Methods: 69 cases of patients with osteoarthritis and 69 cases of healthy volunteers were regarded as research objects. Etidronate disodium had been continuously administrated for 4 w. The patient's bone density reached to the normal value which was regarded as effectiveness of the treatment. The miRNA98b level before and after therapy in blood cells of patients with osteoarthritis and healthy volunteers was detected by real time RT-PCR. The correlation between miRNA98b levels and osteoarthritis was analysed. Results: mRNA level of miRNA98b in blood cells of patients with osteoarthritis was higher than that of healthy volunteers. After being continuously administrated for 2 w, mRNA of miRNA98b in blood cells decreased, there was no significant change in the level of miRNA98b in blood cells of healthy volunteers. The level of miRNA98b in the blood cells of patients with severe osteoarthritis is higher than that in the blood cells of patients with general osteoarthritis, the difference was statistically significant (P<0.05). The level of miRNA98b in the blood cells of patients with osteoarthritis has a positive correlation with the severity of osteoarthritis. Conclusion: MiRNA98b in blood cells of patients with osteoarthritis may be a potential biomarker for osteoarthritis. The level of miRNA98b was correlated with the severity of osteoarthritis.

Biomarkers of hand osteoarthritis.

Hand osteoarthritis (OA) is a common degenerative joint disorder leading to substantial pain and disability. The most severe subtype is erosive hand OA characterized by an abrupt onset, local inflammation, subchondral erosions and worse outcomes than non-erosive disease. Biomarkers of hand OA could help to diagnose the disease earlier, to distinguish patients with erosive and non-erosive forms, to assess disease severity or to predict its future progression. The objective of this review was to summarize the role of potential biomarkers of hand OA. A PubMed search for soluble biomarkers associated with hand OA was performed from inception to June 2017. In total, 21 relevant publications were found and reviewed. These publications identified 20 potential biomarkers of hand OA. C-terminal cross-linking telopeptide of type II collagen, cartilage oligomeric matrix protein, osteocalcin, hyaluronan, urinary pentosidine, vascular cell adhesion molecule 1, monocyte chemotactic protein 1, osteoprotegerin and interleukin 1 have been shown as potential biomarkers for assessing disease severity. C-terminal cross-linking telopeptide of type I collagen, hyaluronan, urinary pentosidine and myeloperoxidase were shown to differentiate between erosive and non-erosive hand OA patients. A number of biomarkers reflecting joint tissue metabolism and inflammation have been studied in hand OA. Some were identified as potential biomarkers of disease severity and progression, others were shown to differentiate between erosive and non-erosive disease. However, further research is necessary to assess the value of biomarkers for use in clinical practice.

Changes in Membrane Receptors and Ion Channels as Potential Biomarkers for Osteoarthritis.

Osteoarthritis (OA), a degenerative joint condition, is currently difficult to detect early enough for any of the current treatment options to be completely successful. Early diagnosis of this disease could increase the numbers of patients who are able to slow its progression. There are now several diseases where membrane protein biomarkers are used for early diagnosis. The numbers of proteins in the membrane is vast and so it is a rich source of potential biomarkers for OA but we need more knowledge of these before they can be considered practical biomarkers. How are they best measured and are they selective to OA or even certain types of OA? The first step in this process is to identify membrane proteins that change in OA. Here, we summarize several ion channels and receptors that change in OA models and/or OA patients, and may thus be considered candidates as novel membrane biomarkers of OA.

Mass spectrometry assays of plasma biomarkers to predict radiographic progression of knee osteoarthritis.

IntroductionBiomarkers to identify osteoarthritis (OA) patients at risk for disease progression are needed. As part of a proteomic analysis of knee synovial fluid from normal and OA patients, differentially expressed proteins were identified that could represent potential biomarkers for OA. This study aimed to use mass spectrometry assays to identify representative peptides from several proteins in synovial fluid and peripheral blood, and assess their levels as biomarkers of OA progression.MethodsMultiplexed high throughput selected reaction monitoring (SRM) assays were developed to measure tryptic peptides representative of 23 proteins in matched serum and synovial fluid samples from late OA subjects at the time of joint replacement. Subsequently plasma samples from the baseline visit of 173 subjects in an observational OA cohort were tested by SRM for peptides from nine of these proteins: afamin, clusterin, cartilage oligomeric matrix protein, hepatocyte growth factor, kallistatin, insulin-like growth factor binding protein, acid labile subunit, lubricin, lumican, and pigment epithelium-derived factor. Linear regression was used to determine the association between the peptide biomarker level at baseline and change in joint space width (ΔJSW) from baseline to 30 months, adjusting for age and sex.ResultsIn the matched cohort, 17 proteins could be identified in synovial fluid and 16 proteins were detected in serum. For the progression cohort, the average age was 62 and average ΔJSW over 30 months was 0.68 mm. A high correlation between different peptides from individual proteins was observed, indicating our assays correctly measured their target proteins. Peptides representative of clusterin, lumican and lubricin showed statistically significant associations with joint space narrowing after adjustment for age and sex. Partial R2 values showed clusterin FMETVAEK and lubricin LVEVNPK peptide biomarkers explains about 2 to 3% of the variability of ΔJSW, similar to that explained by age. A biomarker score combining normalized data for both lubricin and clusterin peptides increased the model R2 to 0.079.ConclusionsOur results suggest that when combined, levels of peptides representative of clusterin and lubricin in plasma are as predictive of OA progression as age. Replication of these findings in other prospective OA cohorts is planned.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0456-6) contains supplementary material, which is available to authorized users.

Selected reaction monitoring assays in mesenchymal stem cells from osteoarthritis patients.

Osteoarthritis (OA) is considered the most prevalent form of arthritis. The aim of this study was to verify potential protein OA biomarkers by applying Selected Reaction Monitoring (SRM) assays to protein extracts obtained from Bone Marrow-Mesenchymal Stem Cells (BM-MSCs) isolated from OA patients.BM aspirates were obtained from the femoral channel of OA patients at the time of surgery and from the femoral channel of hip fracture subjects without OA during hip joint replacement surgery for the treatment of subcapital fracture.SRM results verified the differential expression of several protein biomarkers in BM-MSCs from OA patients.

THU0198 The Alteration of Haptoglobin Chains in Osteoarthritis: New Disease Biomarkers?

BackgroundHaptoglobin (HPT) is a plasma protein that binds free hemoglobin with high affinity and thereby inhibits its oxidative activity. HPT exists in two allelic forms in the human population, which...

Granulocyte population in synovial fluid varies in patients after anterior cruciate ligament reconstruction and positivily correlates with the protein levels of a proinflammatory cytokine, il-1 beta

Granulocyte population in synovial fluid varies in patients after anterior cruciate ligament reconstruction and positivily correlates with the protein levels of a proinflammatory cytokine, il-1 beta

Collagen type III deposition in articular cartilage may be a distinctive biomarker of hip osteoarthritis

Collagen type III deposition in articular cartilage may be a distinctive biomarker of hip osteoarthritis

Heritability assessment of cartilage metabolism. A twin study on procollagen II N-terminal propeptide (PIIANP)

Heritability assessment of cartilage metabolism. A twin study on procollagen II N-terminal propeptide (PIIANP)

Articular Cartilage: Evaluation with Fluid-suppressed 7.0-T Sodium MR Imaging in Subjects with and Subjects without Osteoarthritis

To assess the potential use of sodium magnetic resonance (MR) imaging of cartilage, with and without fluid suppression by using an adiabatic pulse, for classifying subjects with versus subjects without osteoarthritis at 7.0 T. The study was approved by the institutional review board and was compliant with HIPAA. The knee cartilage of 19 asymptomatic (control subjects) and 28 symptomatic (osteoarthritis patients) subjects underwent 7.0-T sodium MR imaging with use of two different sequences: one without fluid suppression (radial three-dimensional sequence) and one with fluid suppression (inversion recovery [IR] wideband uniform rate and smooth truncation [WURST]). Fluid suppression was obtained by using IR with an adiabatic inversion pulse (WURST pulse). Mean sodium concentrations and their standard deviations were measured in the patellar, femorotibial medial, and lateral cartilage regions over four consecutive sections for each subject. The minimum, maximum, median, and average means and standard deviations were calculated over all measurements for each subject. The utility of these measures in the detection of osteoarthritis was evaluated by using logistic regression and the area under the receiver operating characteristic curve (AUC). Bonferroni correction was applied to the P values obtained with logistic regression. Measurements from IR WURST were found to be significant predicators of all osteoarthritis (Kellgren-Lawrence score of 1-4) and early osteoarthritis (Kellgren-Lawrence score of 1 or 2). The minimum standard deviation provided the highest AUC (0.83) with the highest accuracy (>78%), sensitivity (>82%), and specificity (>74%) for both all osteoarthritis and early osteoarthritis groups. Quantitative sodium MR imaging at 7.0 T with fluid suppression by using adiabatic IR is a potential biomarker for osteoarthritis.

Identification of Osteoarthritis Biomarkers by Proteomic Analysis of Synovial Fluid

To use proteomic analysis to identify novel candidate biomarker proteins in synovial fluid for the differential diagnosis of osteoarthritis and rheumatoid arthritis. Synovial fluid samples were analysed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Data were used to generate an artificial neural network (ANN). The identification of one protein peak was confirmed via Western blotting. Fluid samples were analysed from 36 patients with osteoarthritis and 24 with rheumatoid arthritis. In total, three protein peaks (mass-to-charge ratio [m/z] 3893, 10,576 and 14,175 Da) were identified as potential biomarkers for osteoarthritis. The ANN differentiated between osteoarthritis and rheumatoid arthritis with a sensitivity of 89.4% and a specificity of 91.2%. The protein peak at m/z 10 576 was identified as S100 calcium binding protein A12 (S100A12). A combination of SELDI-TOF-MS and ANN identified osteoarthritis biomarkers. SELDI-TOF-MS may be a useful tool in the screening of synovial fluid for osteoarthritis diagnosis.

Metabolic health in families enriched for longevity is associated with low prevalence of hand osteoarthritis and influences OA biomarker profiles

ObjectivesIndividual metabolic characteristics and age-related changes may affect osteoarthritis (OA) risk as well as levels of potential OA biomarkers such as serum cartilage oligomeric protein (sCOMP) and urinary cross-linked C-telopeptide...

Fibulin 3 peptides Fib3‐1 and Fib3‐2 are potential biomarkers of osteoarthritis

This study was undertaken to identify new biomarkers of osteoarthritis (OA) by proteomics analysis and to develop specific immunoassays to detect and quantify them. Proteomics analysis was performed in urine samples from 10 women (mean±SD age 76.0±5.0 years) undergoing knee replacement surgery due to severe OA and 5 healthy women (mean±SD age 25.6±2.6 years). Protein content was analyzed by 2-dimensional differential gel electrophoresis. Protein spots that exhibited an OA:control abundance ratio of ≥1.5 were identified by mass spectrometry. Specific enzyme-linked immunosorbent assays were developed and validated in serum obtained from 236 healthy subjects ages 20-64 years and from 76 patients with severe radiologic knee OA (mean±SD age 68.8±11.9 years). Immunohistochemical analysis was performed on articular cartilage from tibial plateaus. Thirteen proteins within spots that were significantly modified between groups were identified. Two peptides of fibulin 3, named Fib3-1 and Fib3-2, were of particular interest. Two antisera directed against these peptides were used to develop immunoassays. Compared with age-matched healthy subjects, median levels of serum Fib3-1 and Fib3-2 were elevated in OA patients (54.6 pM versus 85.1 pM [P<0.0001] and 144.4 pM versus 191.4 pM [P<0.0001], respectively). Using area under the receiver operating characteristic curve analysis, we demonstrated that Fib3-1 and Fib3-2 levels discriminate between OA and normal populations. Immunostaining revealed the presence of Fib3-1 and Fib3-2 in chondrocytes and in the extracellular matrix of the superficial layer of the fibrillated cartilage. Our findings indicate that Fib3-1 and Fib3-2 are potential biochemical markers for the diagnosis of OA.