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Schema of the cystine-cysteine cycle in knee osteoarthritis. Under excessive oxidative stress, cysteine is oxidized by hydrogen peroxide to cystine and transported into cells via the cystine-glutamate exchange transporter in the plasma membrane, and the transported cystine is intracellularly reduced to cysteine and used for the synthesis of proteins and glutathione. Glutathione has important roles in reducing reactive oxygen species. Increased extracellular cystine levels reflect the presence of oxidative stress in or around cells. Glutamate released via the cystine-glutamate transporter damages the chondrocytes, and high glutamate levels in the synovial fluid are accompanied by severe joint destruction in animal models of osteoarthritis. Although excessive oxidative stress can be controlled via the cystine-cysteine cycle, higher glutamate would also result in worse metabolic conditions for joint homeostasis
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Background
Osteoarthritis (OA) is one of the costliest and most disabling forms of arthritis, and it poses a major public health burden; however, its detailed etiology, pathophysiology, and metabolism remain unclear. Therefore, the purpose of this study was to investigate the key plasma metabolites and metabolic pathways, especially focusing on rad...
Citations
... 17 The actin cytoskeleton controls the phenotypic stability of chondrocytes to a certain extent, and the cartilage phenotype maintains a fine-tuned balance between anabolism and catabolism. The collapse of the actin network and the loss of cartilage phenotypic stability contribute to the destruction of the cartilage matrix of chondrocytes, resulting in irreversible chondrocyte damage and eventually inducing OA. 18,19 The ingestion of abundant cystine may promote the accumulation of glutathione to inhibit inflammation in OA. 20,21 Therefore, disulfidptosis is a novel research direction, and elucidating its mechanisms may help to understand the pathogenesis of OA and its therapeutic targets. ...
Background
Osteoarthritis (OA) is a major cause of human disability. Despite receiving treatment, patients with the middle and late stage of OA have poor survival outcomes. Therefore, within the framework of predictive, preventive, and personalized medicine (PPPM/3PM), early personalized diagnosis of OA is particularly prominent. PPPM aims to accurately identify disease by integrating multiple omic techniques; however, the efficiency of currently available methods and biomarkers in predicting and diagnosing OA should be improved. Disulfidptosis, a novel programmed cell death mechanism and appeared in particular metabolic status, plays a mysterious characteristic in the occurrence and development of OA, which warrants further investigation.
Methods
In this study, we integrated three public datasets from the Gene Expression Omnibus (GEO) database, including 26 OA samples and 20 normal samples. Via a series of bioinformatic analysis and machine learning, we identified the diagnostic biomarkers and several subtypes of OA. Moreover, the expression of these biomarkers were verified in our in-house cohort and the single cell dataset.
Results
Three significant regulators of disulfidptosis (NCKAP1, OXSM, and SLC3A2) were identified through differential expression analysis and machine learning. And a nomogram constructed based on these three regulators exhibited ideal efficiency in predicting early- and late-stage OA. Furthermore, based on the expression of three regulators, we identified two disulfidptosis-related subtypes of OA with different infiltration of immune cells and personalized expression level of immune checkpoints. Notably, the expression of the three regulators was demonstrated in a single-cell RNA profile and verified in the synovial tissue in our in-house cohort including 6 OA patients and 6 normal people. Finally, an efficient disulfidptosis-mediated diagnostic model was constructed for OA, with the AUC value of 97.6923% in the training set and 93.3333% and 100% in two validation sets.
Conclusion
Overall, with regard to PPPM, this study provided novel insights into the role of disulfidptosis regulators in the personalized diagnosis and treatment of OA.
... The application of metabolomics to the study of KOA has identified several biomarkers associated with KOA [18][19][20]. Researchers have also begun to investigate the correlation between biomarkers and the severity of KOA [3,21,22]. Although different metabolites were obtained in these studies due to different sample sources, these findings have led to a better understanding of the pathogenesis of KOA. ...
Background
Metabolomics is a tool to study the pathogenesis of diseases and their associated metabolites, but there are still insufficient metabolomic studies on severe knee osteoarthritis.To investigate the differences in serum metabolites between healthy populations and knee osteoarthritis (KOA) patients in Southern China using widely targeted metabolomics, and to explore biomarkers and their metabolic pathways that could be associated with the severity of KOA.
Methods
There were 10 healthy individuals in the control group and 32 patients with KOA. According to the Kellgren–Lawrence (KL) grading system, KOA was further divided into mild (n = 13, KL grade 1 and 2) and severe (n = 19, KL grade 3 and 4). Serum samples from all participants were collected and analyzed metabolomics based on ultra-performance liquid chromatography/electrospray ionization/tandem mass spectrometry. We screened for differential metabolites between patients and controls, and between mild and severe KOA. We explored the metabolic pathways involved in differential metabolism using the Kyoto Encyclopedia of Genes and Genomes database.
Results
Sixty-one metabolites were differentially expressed in the sera of the patient group compared with the control group (45 upregulated and 16 downregulated). Analysis of the mild and severe KOA groups showed a total of 12 differential metabolites. Receiver operating characteristic curve analysis showed N-alpha-acetyl-L-asparagine was a good predictor of advanced osteoarthritis(OA).Differential metabolites are enriched in multiple pathways such as arachidonic acid metabolism.
Conclusion
Widely targeted metabolomics found that upregulation of the amino acid metabolite N-α-acetyl-L-asparagine was significantly associated with severe KOA and could be a biomarker for predicting severity of KOA. Arachidonic acid metabolism may play an important role in patients with severe KOA.
... 30 Furthermore, plasma cystine, uric acid, and tyrosine were associated with OA severity and effusion synovitis in female volunteers (n = 596). 31 However, a comparison to males is needed to see if these metabolite-OA disease associations are female-selective. Weight is another potential contributing factor to the circulating metabolome. ...
Osteoarthritis (OA) is the most common form of arthritis resulting in joint discomfort and disability, culminating in decline in life quality. Attention has been drawn in recent years to disease-associated molecular biomarkers found in readily accessible biofluids due to low invasiveness of acquisition and their potential to detect early pathological molecular changes not observed with traditional imaging methodology. These biochemical markers of OA have been found in synovial fluid, blood, and urine. They include emerging molecular classes, such as metabolites and noncoding RNAs, as well as classical biomarkers, like inflammatory mediators and by-products of degradative processes involving articular cartilage. Although blood-based biomarkers tend to be most studied, the use of synovial fluid, a more isolated biofluid in the synovial joint, and urine as an excreted fluid containing OA biomarkers can offer valuable information on local and overall disease activity, respectively. Furthermore, larger clinical studies are required to determine relationships between biomarkers in different biofluids, and their impacts on patient measures of OA. This narrative review provides a concise overview of recent studies of OA using these four classes of biomarkers as potential biomarker for measuring disease incidence, staging, prognosis, and therapeutic intervention efficacy.
... 30 Furthermore, plasma cystine, uric acid, and tyrosine were associated with OA severity and effusion synovitis in female volunteers (n = 596). 31 However, a comparison to males is needed to see if these metabolite-OA disease associations are female-selective. Weight is another potential contributing factor to the circulating metabolome. ...
Osteoarthritis (OA) is the most common form of arthritis resulting in joint discomfort and disability, culminating in decline in life quality. Attention has been drawn in recent years to disease-associated molecular biomarkers found in readily accessible biofluids due to low invasiveness of acquisition and their potential to detect early pathological molecular changes not observed with traditional imaging methodology. These biochemical markers of OA have been found in synovial fluid, blood, and urine. They include emerging molecular classes, such as metabolites and noncoding RNAs, as well as classical biomarkers, like inflammatory mediators and by-products of degradative processes involving articular cartilage. Although blood-based biomarkers tend to be most studied, the use of synovial fluid, a more isolated biofluid in the synovial joint, and urine as an excreted fluid containing OA biomarkers can offer valuable information on local and overall disease activity, respectively. Furthermore, larger clinical studies are required to determine relationships between biomarkers in different biofluids, and their impacts on patient measures of OA. This narrative review provides a concise overview of recent studies of OA using these four classes of biomarkers as potential biomarker for measuring disease incidence, staging, prognosis, and therapeutic intervention efficacy.
... The severity of knee OA was graded from 0 to 4 using the Kellgren-Lawrence (KL) score based on joint space narrowing and osteophyte formation. Radiographic OA was defined as the knee with KL grade ≥ 2 [40]. The previous study has established a significant correlation between MME and radiographic OA [3]. ...
Medial meniscus extrusion (MME) refers to the protrusion of the medial meniscus beyond the tibial edge by more than 3 mm, leading to a deficiency of the hoop strain. MME commonly occurs in conjunction with osteoarthritis (OA) or medial meniscal tears (MMT). However, factors associated with concomitant MME in patients with OA or MMT have not been systematically reviewed. This study aims to perform a systematic review and meta-analysis to identify factors associated with concomitant MME in OA or MMT.
The systematic review of the literature was performed according to PRISMA. A literature search was conducted in 4 databases. All original human studies that reported the available evidence on factors associated with concomitant MME in patients with OA or MMT were included. Pooled binary variables were analyzed by odds ratios (OR) and 95% CIs, and pooled continuous variables were evaluated by mean difference (MD) and 95% CIs.
Ten studies on OA (5993 patients) and eight studies on MMT (872 patients) met the inclusion criteria. The overall pooled incidence of MME was 43% (95% CI, 37–50%) for OA, 61% (95% CI 43–77%) for MMT, and 85% (95% CI 72–94%) for medial meniscal root tears (MMRT). For the population with OA, Factors significantly associated with MME included radiographic OA [OR 4.24; 95% CI 3.07–5.84; P < 0.0001], bone marrow lesions [OR, 3.35; 95% CI 1.61–6.99; P = 0.0013], cartilage damage [OR, 3.25; 95% CI 1.60–6.61; P = 0.0011], and higher body mass index (BMI) [MD, 1.81; 95% CI 1.15–2.48; P < 0.0001]. Factors strongly associated with increased risk of MME for MMT included medial meniscal root [OR, 8.39; 95% CI 2.84–24.82; P < 0.0001] and radial tears [OR, 2.64; 95% CI 1.18–5.92; P < 0.0001].
Radiographic OA, bone marrow lesions, cartilage damage, and higher BMI were significantly associated with concomitant MME with OA. Furthermore, medial meniscal root and radial tears were significantly associated with an increased risk of MME in patients with MMT.
IV.
... Biomarkers affecting the function of knee joint tissue cells can be found in SF of patients with KOA in the early stages, including interleukins (ILs), chemokines, growth factors and matrix metalloproteinases (MMPs), etc. Therefore, it has been proposed in many studies [8,9] that such biomarkers can be applied for diagnosis and grading the severity of diseases, in an attempt to predict the progression of OA earlier and carry out the relevant treatment. ...
Objective
To investigate the expression of inflammatory factors IL-6, IL-8, MMP-1, and MMP-3 in the synovial fluid (SF) of patients with osteoarthritis (OA) during electroacupuncture treatment, and further analyze the correlation between inflammatory factors and the function of patients and the severity of osteoarthritis.
Methods
137 patients with knee osteoarthritis (KOA) were collected. 128 patients were eventually enrolled in the study after propensity matching analysis, including 64 patients in the electroacupuncture group and 64 patients in the control group. K-L grading was performed according to X-rays. The patients in the control group were treated with conventional physical rehabilitation therapy. The patients in the electroacupuncture group were treated with 6 weeks of electroacupuncture and conventional physical rehabilitation therapy. The visual analog score (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and Lysholm knee score were compared at three time points: before treatment, 6 weeks after treatment, and 6 months after treatment. The levels of SF inflammatory factors IL-6, IL-8, MMP-1, and MMP-3 were analyzed in both groups at three time points to investigate the correlation between inflammatory factors and functional scores and K-L classification.
Results
The VAS, WOMAC, and Lysholm scores of patients in both groups improved significantly after treatment (P < 0.05). The electroacupuncture group showed a significant reduction in VAS compared to the control group at 6 weeks and 6 months after treatment (P < 0.05). WOMAC scores were significantly lower in the electroacupuncture group compared to the control group at 6 months post-treatment (P < 0.05). Lysholm scores were significantly higher in the electroacupuncture group compared to the control group at 6 weeks and 6 months post-treatment (P < 0.05). The levels of all inflammatory factors decreased significantly in both groups after treatment. The levels of IL-6, IL-8, and MMP-3 were significantly lower in the electroacupuncture group compared with the control group at 6 weeks and 6 months after treatment (P < 0.05). The level of IL-6 was positively correlated with VAS scores (r = 0.45, p < 0.001) and WOMAC (r = 0.3, p < 0.001), and negatively correlated with Lysholm score (r=-0.27, p < 0.001) and K-L classification (r=- 0.54, p < 0.001).The level of IL-8 was positively correlated with VAS (r = 0.32, p < 0.001) and negatively correlated with Lysholm score (r=-0.19, p < 0.0027). The level of MMP-3 was positively correlated with WOMAC score (r = 0.48, p < 0.001). The level of MMP-1 was negatively correlated with K-L classification (r =-0.29, p < 0.001).
Conclusion
IL-6 in SF was associated with pain, impaired function, and the severity of OA. MMP-3 is associated with the severity of OA. IL-6 and MMP-3 are expected to be used as a biomarker for diagnosis, treatment, and determining the prognosis and severity of OA. Electroacupuncture can effectively relieve pain and enhance articular function in patients with KOA. It is a safe and effective method for treating KOA. SF inflammatory factor levels in patients with KOA decreased significantly after electroacupuncture treatment. Electroacupuncture treatment may work by anti-inflammatory effect.
Osteoarthritis (OA) is a common degenerative disorder of the synovial joints and is usually an age-related disease that occurs due to continuous wear and tear of the cartilage in the joints. Presently, there is no proven medical management to halt the progression of the disease in the early stages. The purpose of our systematic review is to analyze the possible metabolites and metabolic pathways that are specifically involved in OA pathogenesis and early treatment of the disease.
The articles were collected from PubMed, Cochrane, Google Scholar, Embase, and Scopus databases. “Knee”, “Osteoarthritis”, “Proteomics”, “Lipidomics”, “Metabolomics”, “Metabolic Methods”, and metabolic* were employed for finding the articles. Only original articles with human or animal OA models with healthy controls were included.
From the initial screening, a total of 458 articles were identified from the 5 research databases. From these, 297 articles were selected in the end for screening, of which 53 papers were selected for full-text screening. Finally, 50 articles were taken for the review based on body fluid: 6 urine studies, 15 plasma studies, 16 synovial fluid studies, 11 serum studies, 4 joint tissue studies, and 1 fecal study. Many metabolites were found to be elevated in OA. Some of these metabolites can be used to stage the OA Three pathways that were found to be commonly involved are the TCA cycle, the glycolytic pathway, and the lipid metabolism.
All these studies showed a vast array of metabolites and metabolic pathways associated with OA. Metabolites like lysophospholipids, phospholipids, arginine, BCCA, and histidine were identified as potential biomarkers of OA but a definite association was not identified, Three pathways (glycolytic pathway, TCA cycle, and lipid metabolic pathways) have been found as highly significant in OA pathogenesis. These metabolic pathways could provide novel therapeutic targets for the prevention and progression of the disease.
Osteoarthritis (OA) stands as a prevalent and progressively debilitating clinical condition globally, impacting joint structures and leading to their gradual deterioration through inflammatory mechanisms. While both non-modifiable and modifiable factors contribute to its onset, numerous aspects of OA pathophysiology remain elusive despite considerable research strides. Presently, diagnosis heavily relies on clinician expertise and meticulous differential diagnosis to exclude other joint-affecting conditions. Therapeutic approaches for OA predominantly focus on patient education for self-management alongside tailored exercise regimens, often complemented by various pharmacological interventions primarily targeting pain alleviation. However, pharmacological treatments typically exhibit short-term efficacy and local and/or systemic side effects, with prosthetic surgery being the ultimate resolution in severe cases. Thus, exploring the potential integration or substitution of conventional drug therapies with natural compounds and extracts emerges as a promising frontier in enhancing OA management. These alternatives offer improved safety profiles and possess the potential to target specific dysregulated pathways implicated in OA pathogenesis, thereby presenting a holistic approach to address the condition’s complexities.
Small nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20 mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group (n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-high group (n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants (P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors (β = −0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy.
Objective:
To highlight the advances over the past year in metabolite/protein biomarkers for osteoarthritis (OA).
Method:
A literature search of five databases including PubMed, Web of Science, Scopus, Ovid Medline, and Embase was performed for studies on metabolite/protein/peptide/biochemical markers for OA published between April 01, 2022 and March 31, 2023. Records were then screened to include only original research articles using directly collected human specimen, in English language, and with full text available. Data from eligible studies were systematically extracted and summarized.
Results:
A total of 1,600 unique records were extracted, out of which 46 fulfilled the inclusion criteria and were used for data extraction. Forty-one of these 46 studies focused on biomarkers for OA/OA severity/progression, four on OA clustering, and one on OA treatment outcomes. Twenty-nine studied protein markers for OA, thirteen studied metabolite markers, and four studied both. While many studies were the validation of the previously reported biomarkers, a number of novel metabolite/protein biomarkers and biomarker panels were reported in the past year. Biomarker panels might be useful to subset OA patients.
Conclusion:
The number of studies on OA clustering is rising. Although validation in larger cohorts is needed in order to utilize reported biomarkers in clinical practice, these discoveries help better understand the pathogenesis of OA, provide insights into possible mechanisms underlying poor treatment outcomes, and aid in developing personalized treatment based on OA subtypes.
