Circulating and Synovial Fluid Heat Shock Protein 70 Are Correlated with Severity in Knee Osteoarthritis

Objective Heat shock proteins are molecules rapidly produced under conditions of environmental stress, and involve in protecting the cells structural integrity and function. Osteoarthritis (OA) is a chronic destructive disorder of the joints manifested by the ongoing deterioration and loss of articular cartilage. The present study aimed to analyze circulating and synovial heat shock protein (Hsp70) values in knee osteoarthritis patients and healthy controls and to determine their relationship with the radiographic grading of the severity of knee OA. Design Seventy-two subjects with knee OA and 30 control participants were recruited. Circulating and joint fluid Hsp70 values were quantified by commercially available enzyme-linked immunosorbent assay. Results Circulating Hsp70 was markedly higher in knee OA patients compared with that of healthy volunteers ( P = 0.01). Correspondingly, synovial fluid Hsp70 was 3-fold greater than paired circulating Hsp70 samples ( P < 0.001). Further analysis revealed that circulating and joint fluid Hsp70 values were significantly related with the radiographic severity of knee OA ( r = 0.413, P < 0.001 and r = 0.658, P < 0.001, respectively). Subsequently, circulating Hsp70 value was directly associated with joint fluid Hsp70 value ( r = 0.704, P < 0.001). Conclusions Circulating and synovial Hsp70 levels were positively correlated with the radiographic severity of knee OA. Hsp70 could represent a potential biochemical marker for predicting the severity and may play a fundamental part in the pathogenic mechanism of knee OA.

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Correlation of synovial fluid HMGB-1 levels with radiographic severity of knee osteoarthritis

Clinical & Investigative Medicine ◽

10.25011/cim.v34i5.15673 ◽

2011 ◽

Vol 34 (5) ◽

pp. 298 ◽

Cited By ~ 24

Author(s):

Zhan-Chun Li ◽

Guang-Qi Cheng ◽

Kong-Zu Hu ◽

Mao-Qiang Li ◽

Wei-Ping Zang ◽

...

Keyword(s):

Synovial Fluid ◽

Knee Osteoarthritis ◽

Disease Severity ◽

Multinomial Logistic Regression ◽

High Mobility ◽

Enzyme Linked Immunosorbent Assay ◽

Grading System ◽

Radiographic Severity ◽

Knee Oa ◽

Radiographic Disease

Purpose: This study measured high-mobility group box 1 (HMGB-1) levels in serum and synovial fluid (SF) in patients with primary knee osteoarthritis (OA) and correlated these levels with radiographic disease severity. Methods: Seventy-eight OA patients and 30 controls were enrolled in this study. All OA patients were scored according to the Kellgren-Lawrence (KL) grading system. HMGB-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: SF HMGB-1 levels were significantly higher in knee OA patients, compared with controls (P < 0.01). Moreover, SF HMGB-1 levels were positively associated with KL scores (P < 0.01). Multinomial logistic regression demonstrated that the SF HMGB-1 level was an independent factor for radiographic severity of OA (P=0.002); however, serum HMGB-1 levels did not differ significantly between OA patients and controls and did not correlate with KL scores (P > 0.05). Conclusion: These results demonstrate that HMGB-1 levels in SF of knee OA patients are independently associated with radiographic disease severity.

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Clusterin Is Associated with Systemic and Synovial Inflammation in Knee Osteoarthritis

Cartilage ◽

10.1177/1947603520958149 ◽

2020 ◽

pp. 194760352095814

Author(s):

Tachatra Ungsudechachai ◽

Sittisak Honsawek ◽

Jiraphun Jittikoon ◽

Wanvisa Udomsinprasert

Keyword(s):

Synovial Fluid ◽

Knee Osteoarthritis ◽

Mrna Expression ◽

Early Stage ◽

Characteristic Curve ◽

Synovial Inflammation ◽

Enzyme Linked Immunosorbent Assay ◽

Knee Oa ◽

Protein Levels ◽

Synovial Tissues

Objectives This study aimed to determine possible associations between transcriptional and translational levels of clusterin (CLU) in the systemic and local joint environments with the severity of knee osteoarthritis (OA) and to investigate CLU mRNA expression in knee OA fibroblast-like synoviocytes (FLSs) stimulated with tumor necrosis factor-α. Design Circulating and synovial fluid CLU levels in 259 knee OA patients were quantified using an enzyme-linked immunosorbent assay. Relative CLU mRNA expression in 50 knee OA synovial tissues and 4 knee OA FLSs was determined using real-time polymerase chain reaction. Results Plasma CLU levels of knee OA patients were significantly higher than paired synovial fluid samples. Compared with early-stage knee OA patients, those with advanced-stage OA had considerably increased plasma and synovial fluid CLU levels. There were significant positive associations of plasma and synovial fluid CLU levels with radiographic severity of knee OA. Plasma CLU levels were directly correlated with its synovial fluid levels and high-sensitivity C-reactive protein levels in the patients. Receiver-operating characteristic curve analysis unveiled the potential utility of plasma CLU as a novel biomarker for knee OA severity (AUC = 0.80), with a sensitivity of 71.4% and a specificity of 73.3%. Marked upregulation of CLU mRNA expression was observed in both the inflamed synovial tissues and FLSs of knee OA. Conclusion Increased CLU mRNA and protein levels in the systemic and local joint environments of knee OA might reflect knee OA severity, especially systemic and synovial inflammation.

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Diagnostic Value of Interleukin-34 as a Novel Biomarker for Severity of Knee Osteoarthritis

Cartilage ◽

10.1177/1947603521990866 ◽

2021 ◽

pp. 194760352199086

Author(s):

Wanvisa Udomsinprasert ◽

Kittaporn Panon ◽

Siraphop Preechanukul ◽

Jiraphun Jittikoon ◽

Artit Jinawath ◽

...

Keyword(s):

Synovial Fluid ◽

Knee Osteoarthritis ◽

Operating Characteristic ◽

Characteristic Curve ◽

Diagnostic Value ◽

Radiographic Severity ◽

Knee Oa ◽

Protein Expressions ◽

Polymerase Chain ◽

Synovial Tissues

Objectives This study aimed to determine whether plasma and synovial fluid interleukin-34 (IL-34), an inflammatory cytokine reportedly implicated in synovial inflammation-induced joint degeneration, were associated with radiographic severity of knee osteoarthritis (OA) patients and could emerge as knee OA biomarkers. Design Ninety-six knee OA patients and 72 healthy controls were recruited. Plasma and synovial fluid IL-34 levels were quantified using ELISA. IL-34 mRNA and protein expressions in inflamed ( n = 15) and noninflamed synovial tissues ( n = 15) of knee OA patients were determined using real-time polymerase chain reaction and immunohistochemistry, respectively. Results Significant increases in plasma and synovial fluid IL-34 levels were found in knee OA patients—especially those with advanced stage ( P < 0.001, P < 0.001, respectively). Both plasma and synovial fluid IL-34 levels were positively associated with radiographic severity ( r = 0.64, P < 0.001; r = 0.50, P < 0.001, respectively). There was a direct link between plasma and synovial fluid IL-34 ( r = 0.64, P < 0.001). Receiver operating characteristic curve analysis uncovered that the optimal cutoff value of plasma IL-34 as a novel biomarker reflecting knee OA severity was defined at 3750.0 pg/mL (AUC = 0.85), with a sensitivity of 83.1% and a specificity of 74.2%. Further analysis revealed that IL-34 mRNA expression was significantly upregulated in inflamed synovium compared with noninflamed synovium obtained from knee OA patients ( P < 0.001), consistent with protein expression analysis demonstrating IL-34 overexpression localized in the lining and sublining layers of inflamed synovium. Conclusions All findings suggest that elevated plasma and synovial fluid IL-34 would reflect knee OA severity and might have potential utility as biomarkers for the disease progression.

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Interleukin-34 Synovial Fluid Was Associated with Knee Osteoarthritis Severity: A Cross-Sectional Study in Knee Osteoarthritis Patients in Different Radiographic Stages

Disease Markers ◽

10.1155/2018/2095480 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5 ◽

Cited By ~ 5

Author(s):

Shuang-Lei Wang ◽

Rui Zhang ◽

Kong-Zu Hu ◽

Mao-Qiang Li ◽

Zhan-Chun Li

Keyword(s):

Synovial Fluid ◽

Knee Osteoarthritis ◽

Crucial Role ◽

Proinflammatory Cytokine ◽

Cross Sectional Study ◽

Enzyme Linked Immunosorbent Assay ◽

Confounding Factors ◽

Sectional Study ◽

Cross Sectional ◽

Knee Oa

Background. Inflammation might play a crucial role in the pathogenesis of osteoarthritis (OA). Interleukin-34 (IL-34) is a well-known proinflammatory cytokine. Objective. The objective of this study was to detect IL-34 levels in serum and synovial fluid (SF) of patients with OA and to investigate their correlation with radiographic and symptomatic severity. Methods. One hundred and eighty-two OA patients and 69 controls were recruited. IL-34 levels were measured by enzyme-linked immunosorbent assay (ELISA). Radiographic and symptomatic severity of OA was reflected by Kellgren-Lawrence (KL) grades and Western Ontario McMaster University Osteoarthritis Index (WOMAC) scores, respectively. Results. SF IL-34 levels were independently associated with the KL grade (B=0.273, 95% CI: 0.150–0.395; P<0.001). SF IL-34 levels were significantly correlated with WOMAC scores (r=0.265, 95% CI: 0.123–0.399; P<0.001). The correlation between SF IL-34 levels and WOMAC scores was still significant after adjusting for confounding factors (B=0.020, 95% CI: 0.001–0.038; P=0.035) in OA patients. Conclusions. We found that IL-34 levels in SF were significantly associated with the radiographic and symptomatic severity of knee OA.

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Synovial Fluid Eotaxin-1 Levels May Reflect Disease Progression in Primary Knee Osteoarthritis Among Elderly Han Chinese: A Cross-Sectional Study

Cartilage ◽

10.1177/1947603518764280 ◽

2018 ◽

Vol 10 (4) ◽

pp. 408-416 ◽

Cited By ~ 1

Author(s):

Bei Li ◽

Yi-Li Zhang ◽

Shou-Yi Yu

Keyword(s):

Synovial Fluid ◽

Knee Osteoarthritis ◽

Disease Progression ◽

Disease Severity ◽

Han Chinese ◽

Clinical Severity ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls ◽

Knee Oa ◽

Significant Difference

Objective The CC chemokine family member eotaxin-1, also named chemokine C-C motif ligand 11 (CCL11), has been detected in knee osteoarthritis (OA) and could induce breakdown of cartilage matrix. This study was performed to investigate the plasma and synovial fluid eotaxin-1 levels with the disease progression in elderly Han Chinese with primary knee OA. Design A total of 143 elderly primary knee OA patients and 135 healthy controls were enrolled in the study. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was performed to evaluate the clinical severity. The radiographic severity was assessed by Kellgren-Lawrence (K-L) grading. Plasma and synovial fluid (SF) eotaxin-1 levels were explored using enzyme-linked immunosorbent assay. The SF levels of matrix metalloproteinase–3 (MMP-3) and interleukin-6 (IL-6) were also examined. Results Elevated plasma eotaxin-1 levels were found in knee OA patients compared with healthy controls. Eotaxin-1 levels in SF of knee OA patients with K-L grade 4 were significantly elevated compared with those with K-L grades 2 and 3. Meanwhile, knee OA patients with K-L grade 3 had significantly increased SF levels of eotaxin-1 compared with those with K-L grade 2. Plasma eotaxin-1 levels in different K-L grading did not reach significant difference. Eotaxin-1 levels in SF of knee OA patients were significantly associated with disease severity evaluated by KL grading criteria. In addition, eotaxin-1 levels in SF were positively related to clinical severity illustrated by WOMAC as well as biochemical markers MMP-3 and IL-6. Conclusions Eotaxin-1 levels in SF instead of plasma, were independently and positively related to the disease severity in elderly knee OA patients. The inhibition of eotaxin-1 and its related signaling pathways may serve as a novel therapeutic approach for OA progression.

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A new antisarcoma strategy: multisubtype heat shock protein/peptide immunotherapy combined with PD-L1 immunological checkpoint inhibitors

Clinical & Translational Oncology ◽

10.1007/s12094-021-02570-4 ◽

2021 ◽

Author(s):

H. Li ◽

X. Sui ◽

Z. Wang ◽

H. Fu ◽

Z. Wang ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Lung Metastasis ◽

Checkpoint Inhibitors ◽

Combined Therapy ◽

Peptide Vaccine ◽

Tumor Environment ◽

Immune Check Point Inhibitor ◽

Shock Proteins ◽

Sarcoma Treatment

AbstractOsteosarcoma, a common malignant tumor in orthopedics, often has a very poor prognosis after lung metastasis. Immunotherapy has not achieved much progress in the treatment because of the characteristics of solid tumors and immune environment of osteosarcoma. The tumor environment is rather essential for sarcoma treatment. Our previous study demonstrated that heat shock proteins could be used as antitumor vaccines by carrying tumor antigen peptides, and we hypothesize that an anti-osteosarcoma effect may be increased with an immune check point inhibitor (PD-L1 inhibitor) as a combination treatment strategy. The present study prepared a multisubtype mixed heat shock protein osteosarcoma vaccine (mHSP/peptide vaccine) and concluded that the mHSP/peptide vaccine was more effective than a single subtype heat shock protein, like Grp94. Therefore, we used the mHSP/peptide vaccine in combination with a PD-L1 inhibitor to treat osteosarcoma, and the deterioration of osteosarcoma was effectively hampered. The mechanism of combined therapy was investigated, and AKT expression participates with sarcoma lung metastasis. This study proposed an antisarcoma strategy via stimulation of the immune system as a further alternative approach for sarcoma treatment and elucidated the mechanism of combined therapy.

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Synovial fluid-derivedYersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells

European Journal of Immunology ◽

10.1002/eji.1830210923 ◽

1991 ◽

Vol 21 (9) ◽

pp. 2139-2143 ◽

Cited By ~ 75

Author(s):

Elisabeth Hermann ◽

Ansgar W. Lohse ◽

Ruurd Van Der Zee ◽

Willem Van Eden ◽

Werner J. Mayet ◽

...

Keyword(s):

T Cells ◽

Heat Shock ◽

Synovial Fluid ◽

Heat Shock Protein ◽

Antigen Presenting Cells ◽

Antigen Presenting

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Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96.

Journal of Experimental Medicine ◽

10.1084/jem.182.3.885 ◽

1995 ◽

Vol 182 (3) ◽

pp. 885-889 ◽

Cited By ~ 249

Author(s):

D Arnold ◽

S Faath ◽

H Rammensee ◽

H Schild

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Heat Shock Protein ◽

Tumor Cells ◽

Mhc Class I ◽

Donor Cell ◽

Class I ◽

Heat Shock Protein Gp96 ◽

Shock Proteins

Vaccination of mice with heat shock proteins isolated from tumor cells induces immunity to subsequent challenge with those tumor cells the heat shock protein was isolated from but not with other tumor cells (Udono, H., and P.K. Srivastava. 1994. J. Immunol. 152:5398-5403). The specificity of this immune response is caused by tumor-derived peptides bound to the heat shock proteins (Udono., H., and P.K. Srivastava. 1993. J. Exp. Med. 178:1391-1396). Our experiments show that a single immunization with the heat shock protein gp96 isolated from beta-galactosidase (beta-gal) expressing P815 cells (of DBA/2 origin) induces cytotoxic T lymphocytes (CTLs) specific for beta-gal, in addition to minor H antigens expressed by these cells. CTLs can be induced in mice that are major histocompatibility complex (MHC) identical to the gp96 donor cells (H-2d) as well as in mice with a different MHC (H-2b). Thus gp96 is able to induce "cross priming" (Matzinger, P., and M.J. Bevan. 1977. Cell. Immunol. 33:92-100), indicating that gp96-associated peptides are not limited to the MHC class I ligands of the gp96 donor cell. Our data confirm the notion that samples of all cellular antigens presentable by MHC class I molecules are represented by peptides associated with gp96 molecules of that cell, even if the fitting MHC molecule is not expressed. In addition, we extend previous reports on the in vivo immunogenicity of peptides associated gp96 molecules to two new groups of antigens, minor H antigens, and proteins expressed in the cytosol.

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hsp26 of Saccharomyces cerevisiae is related to the superfamily of small heat shock proteins but is without a demonstrable function.

Molecular and Cellular Biology ◽

10.1128/mcb.9.11.5265 ◽

1989 ◽

Vol 9 (11) ◽

pp. 5265-5271 ◽

Cited By ~ 59

Author(s):

R E Susek ◽

S L Lindquist

Keyword(s):

Saccharomyces Cerevisiae ◽

Heat Shock ◽

Heat Shock Protein ◽

Mutational Analysis ◽

Small Heat Shock Protein ◽

Major Effect ◽

Selfish Dna ◽

Dna Elements ◽

Cloned Gene ◽

Shock Proteins

Analysis of the cloned gene confirms that hsp26 of Saccharomyces cerevisiae is a member of the small heat shock protein superfamily. Previous mutational analysis failed to demonstrate any function for the protein. Further experiments presented here demonstrate that hsp26 has no obvious regulatory role and no major effect on thermotolerance. It is possible that the small heat shock protein genes originated as primitive viral or selfish DNA elements.

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Διαχρονικές μεταβολές βιοενέργειας, μεταβολισμού και ανοσολογικής απόκρισης στην οξεία φάση της σοβαρής σήψης

10.12681/eadd/44242 ◽

2018 ◽

Author(s):

Άννα-Μαρία Σπανάκη-Μπαρμπουνάκη

Keyword(s):

Body Mass Index ◽

Flow Cytometry ◽

Severe Sepsis ◽

Heat Shock ◽

Energy Expenditure ◽

Systemic Inflammatory Response Syndrome ◽

Enzyme Linked Immunosorbent Assay ◽

Z Scores ◽

Luminescent Assay ◽

Shock Proteins

Εισαγωγή: Το κυτταρικό στρες από σοβαρή σήψη (severe sepsis, SS) ή σύνδρομο συστηματικής φλεγμονώδους απάντησης (Systemic inflammatory response syndrome, SIRS) εκδηλώνεται με οξείες φλεγμονώδεις, ορμονικές, ανοσολογικές και μεταβολικές διαταραχές. Η συσχέτισή τους με πιθανή δυσλειτουργία μιτοχονδρίων δεν έχει επαρκώς μελετηθεί. Σκοπός: Σκοπός της μελέτης ήταν η εκτίμηση των διαχρονικών μεταβολών φλεγμονώδους-ορμονικής αντίδρασης, ενδογενούς-ανοσίας, βιοενέργειας και μεταβολισμού σε ασθενείς, ενήλικες και παιδιά, με σοβαρή σήψη (SS) και η σύγκριση με αντίστοιχες ομάδες ασθενών με SIRS και υγιών (H), ενηλίκων και παιδιών.Υλικά/Μέθοδοι: Μελετήθηκαν 68 παιδιά (SS/18, SIRS/23, H/27) και 79 ενήλικες (SS/23, SIRS/23, H/33) διαχρονικά, την 1, 3η και 5η ημέρα νοσηλείας. Υπολογίστηκαν ο δείκτης μάζας σώματος (Body mass index (BMI) z-scores) και τα scores βαρύτητας νόσου (PeLOD, APACHE, TISS, SOFA). Μετρήθηκαν η καρδιακή συσταλτικότητα (EF, SF), η τροπονίνη (Tn), το γαλακτικό οξύ, η κατανάλωση ενέργειας (Energy expenditure, EE) με Gas Module E-COVX, το ATP στα λευκά αιμοσφαίρια με δοκιμασία λουσιφεράσης (luciferase luminescent assay), τα επίπεδα γλουταμίνης και NO2/NO3 με υγρή χρωματογραφία υψηλής πίεσης (HPLC), τα προϊόντα υπεροξείδωσης λιπιδίων (TBARS) με χρωματομετρική δοκιμασία, η ρεζιστίνη, η αντιπονεκτίνη ορού και οι εξωκυττάριες Heat Shock Proteins (HSP) με την ποσοτική ανοσοενζυμική μέθοδο ELISA (sandwich enzyme-linked immunosorbent assay), και οι ενδοκυττάριες HSP72, HSP90α με κυτταρομετρία ροής (flow cytometry). Αποτελέσματα: Διαχρονικά τόσο σε ενήλικες (ICU) όσο και σε παιδιά (PICU) οι τιμές ρεζιστίνης, αντιπονεκτίνης, εξωκυττάριας HPS72 και 90α παρουσιάζαν σταθερό πρότυπο διέγερσης σε όλη την οξεία φάση των 5 ημέρων. Στη χρονική αυτή περίοδο, οι παράμετροι μεταβολισμού VO2, VCO2, EE παρουσίασαν σταθερό υπομεταβολικό προφίλ, ίδιο σε ενήλικες και παιδιά. Η αυξημένη έκφραση των NO3, NO2, TBARS και αντιπονεκτίνης στη σήψη παρουσίασαν μια πιο ασταθή εικόνα όσον αφορά τη διαχρονική τους έκφραση ανά ηλικιακή ομάδα.Η βιοενέργεια των μιτοχονδρίων ήταν διαχρονικά μειωμένη σε ενήλικες κα παιδιά που δεν επιβίωσαν σε σχέση με εκείνους που επιβίωσαν, και συνοδεύονταν από σημαντικά μειωμένο μεταβολισμό και υπομεταβολικά πρότυπα την 3η και 5η ημέρα (p<0.05). Οι ασθενείς που επιβίωσαν παρουσίαζαν σημαντική διαφοροποίηση των αρχικών τιμών BVR, γαλακτικού, ΕΕ, VO2, VCO2 και μεταβολικού προφιλ σε σύγκριση με ασθενείς που πέθαναν, οι οποίοι έδειξαν αδυναμία ανάκαμψης του υπομεταβολισμού ή της αντιοξειδωτικής κατάστασης την 5η ημέρα. Συμπέρασμα: Η SS χαρακτηρίζεται διαχρονικά, από ισχυρότερη ενδοκυττάρια καταστολή μεταβολισμού, μείωση κατανάλωσης ενέργειας, μείωση των ATP, HPS72, HSP90α, αλβουμίνης, γλουταμίνης και εξωκυττάρια αύξηση φλεγμονωδών ορμονών, ρεζιστίνης και αντιπονεκτίνης και πρωτεϊνών έμφυτης ανοσίας (HSP72). Μια πρώιμη κατάσταση υπομεταβολισμού, με καταστολή βιοενέργειας και ενδογενούς ανοσίας, η οποία και παραμένει διαχρονικά μαζί με συνεχιζόμενη κατάσταση φλεγμονής, με διαχρονικά αυξημένες μεταβολικές ορμόνες και πρωτείνες eHSP72/HSP90α, φαίνεται να ξεχωρίζει τη σήψη από το SIRS, και συνδέεται με αυξημένο κίνδυνο θανάτου.Λέξεις κλειδιά: σήψη, SIRS, βιοενέργεια, HSP, μιτοχόνδρια, μεταβολισμός, θερμιδομετρία, αμινοξέα, οξείδιο του αζώτου, ATP, ρεζιστίνη, αντιπονεκτίνη, τραύμα

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