Expression of granulocyte macrophage-colony stimulating factor and its receptor in the synovium of osteoarthritis patients is negatively correlated with pain

Rheumatology ◽  
2020 ◽  
Vol 59 (11) ◽  
pp. 3452-3457 ◽  
Author(s):  
Eefje M van Helvoort ◽  
Niels Eijkelkamp ◽  
Floris P J G Lafeber ◽  
Simon C Mastbergen
Keyword(s):  
Synovial Tissue ◽  
Knee Pain ◽  
Ex Vivo ◽  
Cartilage Damage ◽  
Synovial Inflammation ◽  
Gm Csf ◽  
Knee Oa ◽  
Analgesic Effects ◽  
Womac Questionnaire ◽  
Tissue Cells

Abstract Objectives The crosstalk between the immune and nervous system in the regulation of OA pain is increasingly becoming evident. GM-CSF signals in both systems and might be a new treatment target to control OA pain. Anti GM-CSF treatment has analgesic effects in OA without affecting synovitis scores, suggesting that treatment effects are not caused by local anti-inflammatory effects. We aimed to evaluate whether expression of GM-CSF and its receptor GM-CSFrα in synovial tissue is linked to synovial inflammation and/or knee pain in knee OA patients. Methods Cartilage and synovial tissue of knee OA patients (n = 20) was collected during total knee replacement. Cartilage damage was evaluated by histology and ex vivo matrix proteoglycan turnover. Synovial inflammation was evaluated by histology and ex vivo synovial production of TNF-α, (PGE2) and nitric oxide (NO). Numbers of synovial tissue cells expressing GM-CSF or GM-CSFrα were determined by immunohistochemistry. Pain was evaluated using WOMAC questionnaire and visual analogue scale (VAS) knee pain. Results Collected cartilage and synovial tissue had a typical OA phenotype with enhanced cartilage damage and synovial inflammation. GM-CSF and GM-CSFrα expressing cells in the synovial sublining correlated negatively with knee pain. Cartilage damage and synovial inflammation did not correlate with knee pain. Conclusion Unanticipated, the negative correlation between synovial tissue cells expressing GM-CSF(r) and OA knee pain suggests that local presence of these molecules does not promote pain, and that the role of GM-CSFr in OA pain is unrelated to local inflammation. Trial registration ToetsingOnline.nl NL18274.101.07.

scholarly journals IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

Cartilage ◽  
2021 ◽  
pp. 194760352110267
Author(s):  
E.M. van Helvoort ◽  
H.M. de Visser ◽  
F.P.J.G. Lafeber ◽  
K. Coeleveld ◽  
S. Versteeg ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Single Molecule ◽  
Mechanical Allodynia ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Synovial Inflammation ◽  
Interleukin 4 ◽  
Analgesic Effects ◽  
Metabolic Dysregulation ◽  
Anti Inflammatory

Objective Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. Design rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats ( n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP ( n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. Results Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration ( P = 0.042) and decreased mechanical allodynia ( P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. Conclusion rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity.

scholarly journals Association of synovial tissue polyfunctional T-cells with DAPSA in psoriatic arthritis

2019 ◽  
Vol 78 (3) ◽  
pp. 350-354 ◽  
Author(s):  
Sarah M Wade ◽  
Mary Canavan ◽  
Trudy McGarry ◽  
Candice Low ◽  
Siobhan C Wade ◽  
...  
Keyword(s):  
T Cells ◽  
Psoriatic Arthritis ◽  
Synovial Tissue ◽  
Ex Vivo ◽  
Cell Suspensions ◽  
Pde4 Inhibitor ◽  
T Helper ◽  
Gm Csf ◽  
Ifn Γ ◽  
Polyfunctional T Cells

ObjectiveThis study examines polyfunctional T-cells in psoriatic arthritis (PsA) synovial tissue and their associations with clinical disease and implications for therapy.MethodsPsA synovial tissue was enzymatically/mechanically digested to generate synovial tissue single cell suspensions. Frequencies of polyfunctional CD4, CD8, T-helper 1 (Th1), Th17 and exTh17 cells, using CD161 as a marker of Th17 plasticity, were determined by flow cytometry in matched PsA synovial tissue and peripheral blood. Synovial T-cell polyfunctionality was assessed in relation to Disease Activity in PSoriatic Arthritis (DAPSA) and in synovial cell suspensions cultured with a current mode of treatment, phosphodiesterase 4 (PDE4) inhibitor.ResultsPsA synovial tissue infiltrating CD4+ T-cells expressed higher levels of interleukin (IL)-17A, interferon gamma (IFN-γ), GM-CSF and CD161, with parallel enrichment of Th1, Th17 and exTh17 T-helper subsets (all p<0.05). Interestingly, a significant proportion of synovial T-cell subsets were triple-positive for GM-CSF, tumour necrosis factor (-TNF), -IL-17 or IFN-γ compared with matched blood (all p<0.05). Importantly, frequencies of polyfunctional T-cells correlated with DAPSA: Th1-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p<0.01), Th17-GM-CSF+/TNF+/IL-17+ (r=0.6, p<0.057) and exTh17-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p=0.0096), with no associations observed for single cytokine-producing T-cells. Following ex vivo culture of PsA synovial tissue cell suspensions, polyfunctional GM-CSF+TNFα+IL-17A+ or/IFN-γ+-producing T-cells (p<0.05), but not single cytokine-producing T-cells, were inhibited with a PDE4 inhibitor.ConclusionThese data demonstrate enrichment of polyfunctional T-cells in PsA synovial tissue which were strongly associated with DAPSA and ex vivo therapeutic response.

scholarly journals Chondroprotective Effects of Hyaluronic Acid-Chitosan Nanoparticles Containing Plasmid DNA Encoding Cytokine Response Modifier A in a Rat Knee Osteoarthritis Model

2018 ◽  
Vol 47 (3) ◽  
pp. 1207-1216 ◽  
Author(s):  
Pang-hu Zhou ◽  
Bo Qiu ◽  
Rong-hui Deng ◽  
Hua-jie Li ◽  
Xiong-feng Xu ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Synovial Tissue ◽  
Plasmid Dna ◽  
Cartilage Damage ◽  
Chitosan Nanoparticles ◽  
Type Ii Collagen ◽  
Synovial Inflammation ◽  
Type Ii ◽  
Dna Encoding ◽  
Response Modifier

Background/Aims: Interleukin (IL)-1β plays an essential role in the pathophysiology of osteoarthritis (OA). Cytokine response modifier A (CrmA) can prevent the generation of active IL-1β. This study aimed to explore the chondroprotective effects of hyaluronic acid-chitosan nanoparticles containing plasmid DNA encoding CrmA (HA/CS-CrmA) in a rat OA model. Methods: HA/CS-CrmA nanoparticles were synthesized through the complex coacervation of cationic polymers. The characteristics, toxicity, and transfection of the nanoparticles were investigated. Furthermore, the potential effects of HA/CS-CrmA nanoparticles were evaluated via a rat anterior cruciate ligament transection (ACLT) model of OA. Cartilage damage and synovial inflammation were assessed by safranin O/fast green and hematoxylin and eosin staining. Type II collagen in cartilage was measured by immunohistochemistry, and the expression levels of IL-1β, matrix metalloproteinase (MMP)-3, and MMP-13 in synovial tissue were detected by western blot. Results: The HA/CS-CrmA nanoparticles, which effectively entrapped plasmid DNA, showed an adequate size (100-300 nm) and a regular spherical shape. The nanoparticles safely transfected synoviocytes and released plasmid DNA in a sustained manner over 3 weeks. Additionally, HA/CS-CrmA nanoparticles significantly inhibited cartilage damage, synovial inflammation, and the loss of type II collagen induced by ACLT. The expression levels of IL-1β, MMP-3, and MMP-13 in synovial tissue were dramatically down-regulated by HA/CS-CrmA nanoparticles. Conclusions: These results suggested that HA/CS-CrmA nanoparticles could attenuate cartilage destruction and protect against early OA by inhibiting synovial inflammation via inhibition of IL-1β generation.

Association of Eccentric Quadriceps Torque With Knee Pain, Physical Function and Extension Lag in Women With Grade ≤ II Knee Osteoarthritis-A Cross-Sectional Study

2021 ◽  
Author(s):  
Fares Arab ◽  
Nishat Quddus ◽  
Sohrab A. Khan ◽  
Ahmad H. Alghadir ◽  
Masood Khan
Keyword(s):  
Knee Osteoarthritis ◽  
Physical Function ◽  
Knee Pain ◽  
Cross Sectional Study ◽  
Rehabilitation Program ◽  
Cross Sectional ◽  
Knee Oa ◽  
Womac Questionnaire ◽  
Grade Ii ◽  
Cross Sectional Design

Abstract Background Knee osteoarthritis (OA) is a prevalent disabling disease among women. Quadriceps weakness is attributed to one of the causes of knee pain (KP) and disability. The study aimed to test the correlation of eccentric quadriceps torque (EQT) with 2 subscales of reduced WOMAC questionnaire (KP and physical function) and extension lag range of motion (ROM) at the knee joint in osteoarthritic women. Methods A cross-sectional design was used. A total of 70 (age 41.1 ± 7.1) female patients having grade ≤ II knee OA participated in the study. Pearson’s correlation coefficient was used to test the correlation between the independent variable (EQT) and dependent variables (2 subscales of reduced WOMAC questionnaire and extension lag in the knee). Results EQT presented a significant moderate negative correlation with the reduced WOMAC subscales (pain r = -0.489, p < 0.01 and physical function r = -0.425, p < 0.01), and low positive correlation with available ROM (r = 0.349, p < 0.01). Conclusions The self-reported symptoms of KP, physical function, and extension lag in the early stages of knee OA in women are associated with EQT. Thus designing a rehabilitation program having eccentric quadriceps strengthening exercises may improve KP and physical activities but further randomized controlled trials are needed to verify this.

scholarly journals AB0069 LORECIVIVINT (SM04690), AN INTRA-ARTICULAR, SMALL-MOLECULE CLK/DYRK1A INHIBITOR THAT MODULATES THE WNT PATHWAY, AS A POTENTIAL TREATMENT FOR MENISCAL INJURIES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1335.2-1335
Author(s):  
T. Seo ◽  
V. Deshmukh ◽  
Y. Yazici
Keyword(s):  
Small Molecule ◽  
Rat Model ◽  
Wnt Pathway ◽  
Ex Vivo ◽  
Meniscal Tear ◽  
Knee Oa ◽  
Meniscus Degeneration ◽  
Anti Inflammatory ◽  
Meniscal Damage

Background:Meniscal injuries, associated with pain, stiffness, and localized swelling, are the most common pathology of the knee with a prevalence of 61 per 100,000.1Meniscal damage is a frequent finding on MRI images of knee osteoarthritis (OA)2; while a meniscal tear can lead to knee OA, knee OA can also lead to a spontaneous meniscal tear.3Efforts to repair meniscal damage have been largely unsuccessful and do not prevent the progression of degenerative changes that lead to knee OA.4The Wnt signaling pathway has been shown to be regulated during meniscal development,5,6suggesting that manipulation of this pathway may influence the regenerative capacity of the meniscus. Lorecivivint (LOR; SM04690) is an intra-articular (IA), small-molecule CLK/DYRK1A inhibitor that modulates the Wnt pathway.Objectives:LOR was evaluated in preclinical studies to determine its protective and anabolic effects in ex vivo explants and in a rat model of chemically induced inflammatory meniscus degeneration.Methods:Effects of LOR (30 nM) on expression of matrix metalloproteinases (MMPs) in cultured rat menisci treated with IL-1B were measured by qPCR. In vivo, LOR activity was evaluated in a rat model of monosodium iodoacetate (MIA) injection-induced inflammatory meniscus degeneration. A single IA injection of MIA was immediately followed by a single IA injection of LOR (0.3 ug) or vehicle. Knees were harvested on Days 1, 4, and 11 and menisci were isolated. Anti-inflammatory effects were evaluated by measuringTNFAandIL6expression by qPCR. Meniscus protection was evaluated by qPCR for MMPs and aggrecanase and anabolic effects by qPCR for collagens.Results:In ex vivo meniscal explants, LOR inhibited expression ofMMP1,MMP3, andMMP13compared to DMSO (P<0.01). In vivo, LOR significantly decreased expression of these MMPs and aggrecanase (P<0.05) compared to vehicle in the rat model of inflammatory meniscus degeneration at Day 4 after MIA injection. In addition, LOR reduced expression of inflammatory cytokinesTNFAandIL6at Day 4 compared to vehicle. Finally, LOR increased expression of collagen types I, II, and III at Day 11 after MIA injection.Conclusion:LOR exhibited protective effects in the meniscus ex vivo and in vivo by reducing the expression of catabolic enzymes compared to control. Anti-inflammatory effects of LOR were demonstrated by inhibition of inflammatory cytokine expression. Compared to vehicle, LOR increased expression of collagens in vivo, indicating potential meniscal anabolic effects. These data support further investigation of LOR as a potential disease-modifying therapy for meniscal injuries.References:[1]Logerstedt D and Snyder-Mackler L.J Orthop Sports Phys Ther. 2010[2]Englund M, et al.Rheum Dis Clin North Am. 2009[3]Englund M, et al.Radiol Clin North Am. 2009[4]von Lewinski, et al.Knee Surg Sports Traumatol Arthrosc. 2007[5]Pazin DE, et al.ORS 2012 Annual Meeting. Paper No. 0221[6]Pazin DE, et al.Dev Dyn. 2012Disclosure of Interests:Tim Seo Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Vishal Deshmukh Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Yusuf Yazici Shareholder of: Samumed, LLC, Grant/research support from: Bristol-Myers Squibb, Celgene, and Genentech, Consultant of: Celgene and Sanofi, Employee of: Samumed, LLC

scholarly journals Generation and Evaluation of Novel Biomaterials Based on Decellularized Sturgeon Cartilage for Use in Tissue Engineering

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 775
Author(s):  
Olimpia Ortiz-Arrabal ◽  
Ramón Carmona ◽  
Óscar-Darío García-García ◽  
Jesús Chato-Astrain ◽  
David Sánchez-Porras ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Ex Vivo ◽  
Cartilage Damage ◽  
Human Mesenchymal Stem Cells ◽  
In Silico Analysis ◽  
Cartilage Tissue ◽  
Advanced Therapy Medicinal Product ◽  
Advanced Therapy ◽  
Novel Scaffold

Because cartilage has limited regenerative capability, a fully efficient advanced therapy medicinal product is needed to treat severe cartilage damage. We evaluated a novel biomaterial obtained by decellularizing sturgeon chondral endoskeleton tissue for use in cartilage tissue engineering. In silico analysis suggested high homology between human and sturgeon collagen proteins, and ultra-performance liquid chromatography confirmed that both types of cartilage consisted mainly of the same amino acids. Decellularized sturgeon cartilage was recellularized with human chondrocytes and four types of human mesenchymal stem cells (MSC) and their suitability for generating a cartilage substitute was assessed ex vivo and in vivo. The results supported the biocompatibility of the novel scaffold, as well as its ability to sustain cell adhesion, proliferation and differentiation. In vivo assays showed that the MSC cells in grafted cartilage disks were biosynthetically active and able to remodel the extracellular matrix of cartilage substitutes, with the production of type II collagen and other relevant components, especially when adipose tissue MSC were used. In addition, these cartilage substitutes triggered a pro-regenerative reaction mediated by CD206-positive M2 macrophages. These preliminary results warrant further research to characterize in greater detail the potential clinical translation of these novel cartilage substitutes.

scholarly journals Mimicking of Blood Flow Results in a Distinct Functional Phenotype in Human Non-Adherent Classical Monocytes

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 748
Author(s):  
Elisa Wirthgen ◽  
Melanie Hornschuh ◽  
Ida Maria Wrobel ◽  
Christian Manteuffel ◽  
Jan Däbritz
Keyword(s):  
Blood Flow ◽  
Shear Flow ◽  
Ex Vivo ◽  
Culture Conditions ◽  
Inflammatory Signaling ◽  
Gm Csf ◽  
Beneficial Effects ◽  
Migratory Capacity ◽  
Ex Vivo Culture ◽  
Static Conditions

Ex vivo culture conditions during the manufacturing process impact the therapeutic effect of cell-based products. Mimicking blood flow during ex vivo culture of monocytes has beneficial effects by preserving their migratory ability. However, the effects of shear flow on the inflammatory response have not been studied so far. Hence, the present study investigates the effects of shear flow on both blood-derived naïve and activated monocytes. The activation of monocytes was experimentally induced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which acts as a pro-survival and growth factor on monocytes with a potential role in inflammation. Monocytes were cultured under dynamic (=shear flow) or static conditions while preventing monocytes' adherence by using cell-repellent surfaces to avoid adhesion-induced differentiation. After cultivation (40 h), cell size, viability, and cytokine secretion were evaluated, and the cells were further applied to functional tests on their migratory capacity, adherence, and metabolic activity. Our results demonstrate that the application of shear flow resulted in a decreased pro-inflammatory signaling concurrent with increased secretion of the anti-inflammatory cytokine IL-10 and increased migratory capacity. These features may improve the efficacy of monocyte-based therapeutic products as both the unwanted inflammatory signaling in blood circulation and the loss of migratory ability will be prevented.

scholarly journals The Rationale for the Intra-Articular Administration of Clodronate in Osteoarthritis

2021 ◽  
Vol 22 (5) ◽  
pp. 2693
Author(s):  
Antimo Moretti ◽  
Marco Paoletta ◽  
Sara Liguori ◽  
Walter Ilardi ◽  
Francesco Snichelotto ◽  
...  
Keyword(s):  
Animal Models ◽  
Scoping Review ◽  
Cartilage Damage ◽  
Joint Inflammation ◽  
Mechanisms Of Action ◽  
Clodronic Acid ◽  
Clinical Role ◽  
Knee Oa ◽  
Positive Effects ◽  
Scoping Reviews

Background: Several pharmacological therapeutic approaches have been proposed to manage osteoarthritis (OA), including intra-articular (IA) injections. Although the discovery of clodronate, a bisphosphonate, dates back to the 1960s and the effects of its IA administration have been investigated for decades in animal models, mechanisms of action of this drug are not quite clear, particularly in OA. This scoping review is an overview of the biological as well as the clinical role of clodronic acid in OA. Method: A scoping review based on the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) model was performed to characterize the mechanisms of action of IA clodronate in OA and to evaluate its efficacy from a clinical point of view. Results: Several effects of clodronate have been observed in animal models of OA, including depletion of synovial lining cells that results in reduced production of chemokines (IL-1, TNF- α), growth factors (TGF-β, BMP 2/4), and metalloproteases (MMP 2/3/9); prevention of cartilage damage, synovial hyperplasia, and proteoglycans loss; reduction in joint inflammation, joint swelling, and osteophyte formation. From a clinical perspective, patients with knee OA treated with IA clodronate experienced improvements in pain and joint mobility. Conclusion: Clodronate appears to have different mechanisms of action interfering with the pathogenic processes contributing to OA development and progression. This intervention demonstrated positive effects for patients affected by knee OA.

Neurophysiological basis for neurogenic-mediated articular cartilage anabolism alteration

2001 ◽  
Vol 280 (1) ◽  
pp. R115-R122 ◽  
Author(s):  
Elvire Gouze-Decaris ◽  
Lionel Philippe ◽  
Alain Minn ◽  
Philippe Haouzi ◽  
Pierre Gillet ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Ex Vivo ◽  
Cartilage Damage ◽  
Intrathecal Injection ◽  
Chronic Administration ◽  
C Fibers ◽  
Glutamatergic Synaptic Transmission ◽  
C Fiber ◽  
Fiber Stimulation ◽  
Neurophysiological Basis

This study was designed to investigate the pathways involved in neurogenic-mediated articular cartilage damage triggered by a nonsystemic distant subcutaneous or intra-articular inflammation. The cartilage damage was assessed 24 h after subcutaneous or intra-articular complete Freund's adjuvant (CFA) injection measuring patellar proteoglycan (PG) synthesis (ex vivo [Na2 35SO4] incorporation) in 96 Wistar rats. Unilateral subcutaneous or intra-articular injection of CFA induced significant decrease (25–29%) in PG synthesis in both patellae. Chronic administration of capsaicin (50 mg · kg−1 · day−1 during 4 days), which blunted the normal response of C fiber stimulation, prevented the bilateral significant decrease in cartilage synthesis. Similarly, intrathecal injection of MK-801 (10 nmol/day during 5 days), which blocked the glutamatergic synaptic transmission at the dorsal horn of signal originating in primary afferent C fibers, eliminated the CFA-induced PG synthesis decrease in both patellae. Chemical sympathectomy, induced by guanethidine (12.5 mg · kg−1 · day−1 during 6 wk), also prevented PG synthesis alteration. Finally, compression of the spinal cord at the T3-T5 level had a similar protective effect on the reduction of [Na2 35SO4] incorporation. It is concluded that the signal that triggers articular cartilage synthesis damage induced by a distant local inflammation 1) is transmitted through the afferent C fibers, 2) makes glutamatergic synaptic connections with the preganglionic neurons of the sympathetic system, and 3) involves spinal and supraspinal pathways.

scholarly journals Prevalence and overlap of doctor-diagnosed knee OA, frequent knee pain and radiographic knee OA in Sweden

2014 ◽  
Vol 22 ◽  
pp. S206-S207
Author(s):  
A. Turkiewicz ◽  
M. Gerhardsson de Verdier ◽  
G. Engström ◽  
L.S. Lohmander ◽  
M. Englund
Keyword(s):  
Knee Pain ◽  
Knee Oa
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