Systemic Proteomic Analysis Reveals Distinct Exosomal Protein Profiles in Rheumatoid Arthritis

Objective. Rheumatoid arthritis (RA) is a complex disease with unknown pathogenesis. In recent years, fewer have paid attention to the broad spectrum of systemic markers of RA. The aim of this study was to identify exosomal candidate proteins in the pathogenesis of RA. Methods. Totally, 12 specimens of plasma from 6 RA patients and 6 age- and gender-matched controls from the Chinese population were obtained for nanoscale liquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS) analysis to identify exosomal profiles. Results. A total of 278 exosomal proteins were detected. Among them, 32 proteins were significantly upregulated ( FC ≥ 2.0 and P < 0.05 ) and 5 proteins were downregulated ( FC ≤ 0.5 and P < 0.05 ). Bioinformatics analysis revealed that transthyretin (TTR), angiotensinogen (AGT), lipopolysaccharide-binding protein (LBP), monocyte differentiation antigen CD14 (CD14), cartilage oligomeric matrix protein (COMP), serum amyloid P (SAP/APCS), and tenascin (TNC) can interact with each other. Subsequently, these cross-linked proteins may be mainly involved in the inflammatory-related pathways to mediate the onset of RA. Noteworthy, the LBP/CD14 complex can promote the expression of IL-8 and TNF-α, eventually leading to the development of RA. Conclusions. Our findings suggest distinct plasmatic exosomal protein profiles in RA patients. These proteins not only take important parts in the vicious circle in the pathogenic process of RA but also serve as novel biomarkers in RA diagnosis and prognosis.

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Significance of Expression of miR-365, Cartilage Oligomeric Matrix Protein and Inflammatory Factors in Knee Osteoarthritis

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2366 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1065-1069

Author(s):

Ren Lin ◽

Jinglai Xue ◽

Junqin Qiu

Keyword(s):

Knee Osteoarthritis ◽

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Serum Levels ◽

Inflammatory Factors ◽

Control Group ◽

Observation Group ◽

Logistic Analysis ◽

Tnf Α ◽

And Gender

This study is to investigate the high expression of miR-365, cartilage oligomeric matrix protein (COMP) and inflammatory factors in knee osteoarthritis and their correlation with disease activity. The 94 patients with knee osteoarthritis were selected as the observation group. Controls were 94 healthy people matched according to the age and gender of the observation group. The expression levels of blood miR-365, cartilage oligomeric matrix protein, and the inflammatory IL-6 and TNF-α were compared between two groups and correlations between these indicators and Lysholm knee scores were determined. The serum levels of miR-365, cartilage oligomeric matrix protein and the inflammatory factors IL-6 and TNF-α in osteoarthritis patients exceeded those in the normal control group (P < 0 05), and miR-365 was positively correlated with cartilage oligomeric matrix protein and IL-6 and TNF-α (P < 0 05). In addition, the positive correlation was found between the Lysholm osteoarthritis score and the above factors (P < 0 05). Finally, logistic analysis of elevated peripheral blood miR-365 and COMP is an independent risk factor for osteoarthritis. MiR-365, COMP and inflammatory factors IL-6 and TNF-α are highly expressed in knee osteoarthritis.

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Effects of Obesity Reduction on Physical Function, Inflammation and Osteoarthritis in Older Adults

Innovation in Aging ◽

10.1093/geroni/igab046.3687 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 1041-1041

Author(s):

Michael Borack ◽

Kathryn Porter Starr ◽

Connie Bales ◽

Jamie Rincker ◽

Lou DeFrate ◽

...

Keyword(s):

Older Adults ◽

Weight Loss ◽

Physical Function ◽

Matrix Protein ◽

Cartilage Damage ◽

Blood Biomarkers ◽

Inflammatory Damage ◽

Age Related ◽

Tnf Α ◽

Novel Biomarkers

Abstract Age-related increases in chronic inflammation lead to reduced physical function via damage to muscle and joints and contribute to osteoarthritis (OA) risk. Obesity in older adults with OA further exacerbates inflammatory damage. Whether obesity reduction can lessen inflammation and improve OA is unknown; however, novel biomarkers may provide an answer. We completed a 6-mo. weight loss intervention (-500 kcal/day), studying blood biomarkers of inflammation and cartilage damage along with physical function in obese older adults with (OA+; n=39) and without an OA diagnosis (OA-; n=20). Participants were aged > 60 yrs (mean = 70.2±6.0) and obese (BMI =34.6±4.7 kg/m2). At endpoint, weight loss was -6.3±4.0% and -5.8±4.1% in OA+ and OA-, respectively, with no group difference. Change scores for function for OA+ and OA- were: Short Physical Performance Battery score (+1.7±1.3 and +2.1±1.5), 8 ft up and go (-0.7±1.0 and -0.9±1.12 sec) and 6 min walk (+31.4±105.1 and +39.5±57.4 meters). All improved from baseline (p<0.05), with no group difference. Concerning blood biomarkers, there was a decrease (p<0.05) in cartilage oligomeric matrix protein (COMP: OA biomarker), indicating a potential benefit for OA. Change in COMP also differed between groups; OA- had a greater (p<0.05) reduction than OA+. Pooled results showed improved adiponectin (p<0.05), with no group difference. There were no changes for CRP, CTX-1, IL-6 and TNF-α. Our novel findings link early intervention with better reduction of OA risk and inflammation in obese older adults and also show important benefits for improved physical function regardless of OA status.

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Systemic Proteomic Analysis Reveals Distinct Exosomal Proteins Profiles in Rheumatoid Arthritis

10.21203/rs.3.rs-95581/v1 ◽

2020 ◽

Author(s):

Qiu Qin ◽

Ronghua SONG ◽

Peng DU ◽

Chaoqun GAO ◽

Qiuming YAO ◽

...

Keyword(s):

Signaling Pathway ◽

Regulatory Networks ◽

Matrix Protein ◽

Complex Disease ◽

Interaction Network ◽

Nf Kappa B ◽

Regulatory Pathways ◽

And Gender ◽

Underlying Mechanisms ◽

Pathway Analyses

Abstract BackgroundRheumatoid arthritis (RA) is a heterogeneous and complex disease characterized by autoantibodies production and inflammation of the synovium. Its underlying mechanisms remain elusive. In recent years, exosomes have emerged as non-invasive biomarkers in diverse diseases. Due to its various inflammatory and immunological functions, some studies highlighted abnormalities of exosomes in RA, but fewer have paid attention to the broad spectrum of potential systemic markers of RA. The aim of this study was to identify exosomal candidate proteins in the pathogenesis of RA using systemic proteomic method. MethodsTotally 12 specimens of plasma from 6 RA patients and 6 age-and gender-matched controls from the Chinese population were obtained for nanoscale liquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS) analysis to identify differentially expressed proteins (DEPs) in exosomes. Gene ontology (GO), protein interaction network (PPI) and KEGG pathway analyses were used in subcellular localization analysis. ResultsA total of 278 exosomal proteins were detected. Among them, 32 proteins were significantly upregulated (FC≥2.0 and P<0.05) and 5 proteins were downregulated (FC≤0.5 and P<0.05). Most of these DEPs were immunoglobullins (Igs). Bioinformatics analysis indicated that these Igs are involved in inflammatory response of RA through diverse immune regulatory pathways, such as NF-kappa B signaling pathway. PPI analysis revealed that transthyretin (TTR, P02766), angiotensinogen (AGT, P01019), lipopolysaccharide-binding protein (LBP, P18428), monocyte differentiation antigen CD14 (CD14, P08571), cartilage oligomeric matrix protein (COMP, P49747), serum amyloid P (SAP/APCS, P02743) and tenascin (TNC, P24821) can interact with each other or may form a regulatory networks. Subsequently, these cross-linked proteins may mainly involve in the NF-kappa B signaling pathway or inflammatory-related pathways to mediate the onset of RA. Noteworthy, among these exosomal DEPs, the complex composed of LBP and CD14 is involved in NF-kappa B signaling pathway, resulting in promoted expression of IL-8, TNF-α, and eventually leading to the development of RA.ConclusionsOur findings suggest distinct plasmic exosomal protein profiles in RA patients. These proteins not only take important parts in the vicious circle in the pathogenic process of RA, but also serve as novel biomarkers in RA diagnosis and prognosis.

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Relationship Between Cartilage Oligomeric Matrix Protein Level and Helper T Cell 17/regulatory T Cell Balance in Patients With Rheumatoid Arthritis

10.21203/rs.3.rs-46077/v1 ◽

2020 ◽

Author(s):

Rong HAN

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Treg Cells ◽

Control Group ◽

Helper T Cell ◽

Tnf Α ◽

Factor Α ◽

Cell Balance

Abstract Objective To explore the correlation among the level of cartilage oligomeric matrix protein(COMP) as well as the balancing relationship of helper T cell 17(Th17) /regulatory T cells(Treg) of serum in patients with Rheumatoid Arthritis (RA). Methods 40 patients with RA in the Second Hospital of Shanxi Medical University from May 2019 to May 2020 were selected as RA group, while 40 healthy subjects were collected as a control group. After collecting their serum, the figure of Th17, as well as Treg cells, were encountered by flow cytometry(FC), and the proportion of Th17/Treg was counted. Cytometric was also used to detect serum interleukin(IL)-17, IL-10 and IL-6 concentration. Enzyme-linked immunosorbent (ELISA)was also applied to track down the concentrations of COMP as well as tumor necrosis factor-α(TNF-α). All indicators above were considered among groups, and the interrelationship between COMP and the expression of various cells as well as related cytokines was analyzed. Results The concentration of COMP, Th17 and Th17/Treg in RA group were higher than those in the control group, while Treg was lower than that in the control group, and the variation was statistically weighty(P<0.05). The levels of IL-17, IL-6 and TNF-α in RA group were higher than those in the control group, while the concentration of IL-2 was smaller than that of the control group, the differences were statistically weighty(P<0.01). Interrelationship analysis displayed that COMP was undeniably correlated with Th17, Th17/Treg, IL-17, IL-6 as well as TNF-α levels(r =0.687, 0.478, 0.759, 0.903, 0.813, all P<0.01). There was a negative correlation between the levels of COMP and Treg, IL-2(r =-0.356, -0.455, all P<0.01). Conclusion Compared with healthy people, COMP in peripheral blood of patients with RA is abnormally high, and there is obvious T cell immune abnormality, suggesting that COMP may participate in the development of RA by regulating Th17/Treg balance.

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Clinical Biomarkers and Pathogenic-Related Cytokines in Rheumatoid Arthritis

Journal of Immunology Research ◽

10.1155/2014/698192 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 17

Author(s):

Xiaoyin Niu ◽

Guangjie Chen

Keyword(s):

Rheumatoid Arthritis ◽

Side Effects ◽

Joint Damage ◽

Unknown Etiology ◽

Disease Development ◽

Diagnosis And Prognosis ◽

Clinical Biomarkers ◽

Relieve Pain ◽

Novel Biomarkers ◽

Made In

Rheumatoid arthritis (RA) is a common autoimmune disease with unknown etiology and pathogenesis. Although major therapeutic advances have been made in recent years, there is no cure for the disease. Current medications mainly reduce inflammation in order to relieve pain and slow joint damage, but many have potentially serious side effects. Therefore, to find specific biomarkers will benefit both RA patients to find relief from the disease and physicians to monitor the disease development. A number of biomarkers have been discovered and used clinically, and others are still under investigation. The autoantibodies, which are widely used in diagnosis and prognosis, novel biomarkers, which reflect clinical disease activity, and newly found biomarkers and pathogenic-related cytokines are discussed in this review.

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Relations of Serum COMP to Cardiovascular Risk Factors and Endothelial Function in Patients with Rheumatoid Arthritis Treated with Methotrexate and TNF-α Inhibitors

The Journal of Rheumatology ◽

10.3899/jrheum.111401 ◽

2012 ◽

Vol 39 (7) ◽

pp. 1341-1347 ◽

Cited By ~ 6

Author(s):

GUNNBJØRG HJELTNES ◽

IVANA HOLLAN ◽

ØYSTEIN FØRRE ◽

ALLAN WIIK ◽

TORSTEIN LYBERG ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Cardiovascular Risk ◽

Endothelial Function ◽

Cardiovascular Risk Factors ◽

Matrix Protein ◽

Positive Association ◽

Protein S ◽

Cartilage Destruction ◽

Tnf Α

Objective.To examine whether serum level of cartilage oligomeric matrix protein (S-COMP) is related to methotrexate (MTX) or to MTX and tumor necrosis factor-α (TNF-α) combination treatment for rheumatoid arthritis (RA); and to investigate whether S-COMP is related to cardiovascular risk factors including endothelial dysfunction and level of anticitrullinated protein antibodies (ACPA) in patients with RA.Methods.Clinical and laboratory measures, including S-COMP and reactive hyperemic index (RHI), were examined in 55 consecutive patients with RA starting with either MTX (n = 34) or MTX and anti-TNF-α treatment (n = 21) at baseline, and after 6 weeks and 6 months.Results.S-COMP was similar in the 2 treatment regimens during followup. We found a positive relationship between S-COMP at baseline and the use of disease-modifying antirheumatic drugs the last year preceding the study (p = 0.001), and a negative relation to current use of systemic glucocorticosteroids (p = 0.044). The nonsignificant change in S-COMP between baseline and the 6-month followup was positively and independently related to change in ACPA level (p = 0.009). There was no significant association between RHI and level of S-COMP at baseline.Conclusion.The cartilage turnover marker S-COMP did not change significantly after 6 months’ treatment with MTX with or without a TNF-α inhibitor in patients with RA. The positive association between S-COMP and ACPA suggests that these factors might interact, and could both be contributors to an unknown link between inflammation and cartilage destruction in patients with RA. S-COMP was not related to endothelial function in patients with RA, or to other cardiovascular risk factors studied. Clinical Trials registration numberNCT00902005.

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The pulmonological manifestations of rheumatoid arthritis

Orvosi Hetilap ◽

10.1556/oh.2008.28385 ◽

2008 ◽

Vol 149 (29) ◽

pp. 1355-1361

Author(s):

György Bernscherer ◽

Csaba Karabélyos ◽

Zsolt Tarján

Keyword(s):

Rheumatoid Arthritis ◽

Hodgkin Lymphoma ◽

Non Hodgkin Lymphoma ◽

Tnf Α

A szerzők összefoglaló közleményükben az irodalmi adatok figyelembevételével áttekintik a rheumatoid arthritis primer és szekunder pulmonalis szövődményeit. A rheumatoid arthritis gyógyszeres terápiájának pulmonológiai szövődményei közül kiemelik a betegségmódosító antireumatikus szereket, amelyek közül kitérnek a methotrexat indukálta tüdőgyógyászati kórképekre. A methotrexat szinte majdnem minden additív hatású kettős és hármas – O’Dell-séma – kombinációs terápiában szerepel, ezért is fontos e gyógyszer okozta pulmonalis szövődmények időben történő felismerése. A reumatológusok számára egyre nagyobb kihívást jelent a methotrexattal szemben rezisztens rheumatoid arthritis kezelése. A biológiai terápiás szerek citokinantagonistaként, TNF-α-blokkolás révén fejtik ki hatásukat, és a betegségmódosító antireumatikus szerekhez képest hatásosabban tudják fékezni a betegség progresszióját. Ezek a biológiai válaszmódosító szerek. Főbb képviselőik az infliximab, az adalimumab és az etanercept. A szerzők végül foglalkoznak a biológiai válaszmódosító szerek okozta szekunder pulmonalis szövődményekkel: a pulmonalis tuberculosissal, a bakteriális tracheobronchitisszel, a bakteriális pneumoniával, bronchiectasiával és pulmonalis oedemával, a rapid progresszív fibrotizáló alveolitisszel, valamint a coccidiomycosissal. Az Arizona, Kalifornia, Nevada területén élő, biológiai válaszmódosító szerekkel végzett terápiában részesülő rheumatoid arthritises betegek mintegy 3%-ánál várható a 15%-os halálozással járó pulmonalis és szisztémás gombafertőzés – coccidiomycosis – kialakulása. A gyakori földrengések következtében a talajból a légtérbe kerülő spórák betegítik meg a gyógyszeres terápia miatt immunszupprimált egyéneket. A szerzők felhívják a figyelmet, hogy az előbb említett endémiás, valamint egyéb földrengésaktív területre utazó, biológiai terápiában részesülő betegek potenciális fertőzésveszélynek vannak kitéve, amely miatt a betegek ez irányú tájékoztatása a kezelőorvos részéről elengedhetetlen. A biológiai válaszmódosító szerek újabb és újabb csoportjainak kipróbálása és felhasználása a közeljövőben várható rheumatoid arthritisben. Jelenleg a TNF-α-gátló kezelésre nem reagáló betegeknél lehetőség van a non-Hodgkin-lymphoma terápiájában használatos B-lymphocyta-gátló rituximab alkalmazására. Ez utóbbi citokin rheumatoid arthritisben történő felhasználása során észlelt pulmonalis szövődményeiről még nem rendelkezünk elegendő ismerettel. Napjaink antireumatikus terápiái a betegek életminőségének jelentős javulását eredményezik, miközben az egyre korszerűbb kezelési módok a pulmonalis szövődmények körét gyarapítják.

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Genetic Variation in TNF-α, its Relation with Inflammatory Biomarkers and Susceptibility to Rheumatoid Arthritis

Annals of Immunology & Immunotherapy ◽

10.23880/aii-16000122 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Khadiga Ahmed Ismail

Keyword(s):

Rheumatoid Arthritis ◽

Serum Level ◽

Functional Disability ◽

Serum Levels ◽

Amplification Refractory Mutation System ◽

Reactive Protein ◽

Tnf Α ◽

Mutation System ◽

Potential Factor ◽

Factor Α

Background: Tumor necrosis Factor-α (TNF-α) is encoded and controlled by TNF-α gene, which is involved in rheumatoid arthritis (RA) susceptibility. This research aimed to identify genetic variations of TNF-α (G308A) and to establish its association with inflammatory markers in Rheumatoid Arthritis predisposition. Methods: In the present study, fifty RA patients and fifty volunteers were involved and evaluated for the C-reactive protein, rheumatoid factor, and TNF-α were estimated by ELISA, Erythrocyte Sedimentation Rate (ESR) by Wintergreen method and for TNF-α-308 G>A polymorphism by polymerase chain reaction with amplification refractory mutation system (PCR-ARMS). Results: The CRP, RF, ESR and TNF-α were significantly elevated in RA patients relative to controls. The serum level TNF-α was also significantly elevated in female patients and in patients ≥50 years. Analysis of TNF-308 gene polymorphism revealed that GG genotypes were more prevalent in RA patients than in the healthy individuals and that GG genotype may be a potential factor to RA. The G allele was more common in RA than in the control. Elevated TNF-α serum levels were significantly associated the GG genotype and functional disability in RA patients. Conclusion: TNF-α promoter 308polymorphism GG genotype may be considered as a risk factor for RA and the TNF-α serum level was significantly related to the functional disability in the disease.

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Exosome: An Emerging Source of Biomarkers for Human Diseases

Current Molecular Medicine ◽

10.2174/1566524019666190429144310 ◽

2019 ◽

Vol 19 (6) ◽

pp. 387-394 ◽

Cited By ~ 4

Author(s):

Li Xu ◽

Long-Fei Wu ◽

Fei-Yan Deng

Keyword(s):

Breast Milk ◽

Intercellular Communication ◽

Translational Medicine ◽

Disease Diagnosis ◽

Human Diseases ◽

Isolation And Identification ◽

Biomarker Identification ◽

Biological Features ◽

Diagnosis And Prognosis ◽

Novel Biomarkers

Exosomes are 30-120nm long endocytic membrane-derived vesicles, which are secreted by various types of cells and stably present in body fluids, such as plasma, urine, saliva and breast milk. Exosomes participate in intercellular communication. Recently accumulative studies have suggested that exosomes may serve as novel biomarkers for disease diagnosis and prognosis. Herein, we reviewed the biological features of exosomes, technologies for exosome isolation and identification, as well as progress in exosomal biomarker identification, highlighting the relevance of exosome to human diseases and significance and great potential in translational medicine.

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