scholarly journals Impact of Mechanical Load on the Expression Profile of Synovial Fibroblasts from Patients with and without Osteoarthritis

2019 ◽  
Vol 20 (3) ◽  
pp. 585 ◽  
Author(s):  
Agnes Schröder ◽  
Ute Nazet ◽  
Dominique Muschter ◽  
Susanne Grässel ◽  
Peter Proff ◽  
...  
Keyword(s):  
Mechanical Loading ◽  
Mechanical Load ◽  
Synovial Fibroblasts ◽  
Gene And Protein Expression ◽  
Factor Expression ◽  
Proinflammatory Factor ◽  
Cox 2 ◽  
Pg E2 ◽  
Proinflammatory Factors

Osteoarthritis (OA) affects the integrity of the entire joint including the synovium. The most abundant cells in the synovium are fibroblasts (SF). Excessive mechanical loading might contribute to OA pathogenesis. Here, we investigate the effects of mechanical loading on SF derived from non-OA (N-SF) and OA patients (OA-SF). We treated N-SF and OA-SF with or without mechanical loading for 48h after 24h of preincubation. Then we assessed gene and protein expression of proinflammatory factors (TNFα, COX-2, PG-E2, IL-6), extracellular matrix (ECM) components (COL1, FN1) and glycosaminoglycans (GAGs) via RT-qPCR, ELISA, DMMB assay and HPLC. Mechanical loading significantly increased TNFα and PG-E2 secretion by N-SF and OA-SF, whereas in OA-SF IL-6 secretion was reduced. COL1 and FN1 secretion were downregulated in N-SF during loading. OA-SF secreted less COL1 compared to N-SF under control conditions. In contrast, OA-SF in general expressed more FN1. GAG synthesis was upregulated in N-SF, but not in OA-SF during loading with OA-SF displaying a higher charge density than N-SF. Mechanical loading enhanced proinflammatory factor expression and GAG synthesis and decreased secretion of ECM components in N-SFs, indicating a contributing role of SF to OA development.

scholarly journals ApoL1 renal risk variants induce aberrant THP-1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase-2

2018 ◽  
Vol 315 (1) ◽  
pp. F140-F150 ◽  
Author(s):  
Hewang Lee ◽  
Hila Roshanravan ◽  
Ying Wang ◽  
Koji Okamoto ◽  
Junghwa Ryu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Specific Inhibitor ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Monocyte Differentiation ◽  
Eicosanoid Production ◽  
Gene And Protein Expression ◽  
Cox 2 ◽  
Tgf Β1

Apolipoprotein L1 ( ApoL1) genetic variants are strongly associated with kidney diseases. We investigated the role of ApoL1 variants in monocyte differentiation and eicosanoid production in macrophages, as activated tissue macrophages in kidney might contribute to kidney injury. In human monocyte THP-1 cells, transient overexpression of ApoL1 (G0, G1, G2) by transfection resulted in a 5- to 11-fold increase in CD14 and CD68 gene expression, similar to that seen with phorbol-12-myristate acetate treatment. All ApoL1 variants caused monocytes to differentiate into atypical M1 macrophages with marked increase in M1 markers CD80, TNF, IL1B, and IL6 and modest increase in the M2 marker CD163 compared with control cells. ApoL1-G1 transfection induced additional CD206 and TGFB1 expression, and ApoL1-G2 transfection induced additional CD204 and TGFB1 expression. Gene expression of prostaglandin E2 (PGE2) synthase and thromboxane synthase and both gene and protein expression of cyclooxygenase-2 (COX-2) were increased by ApoL1-G1 and -G2 variants compared with -G0 transfection. Higher levels of PGE2 and thromboxane B2, a stable metabolite of thromboxane A2, and transforming growth factor (TGF)-β1 were released into the supernatant of cultured THP-1 cells transfected with ApoL1-G1 and -G2, but not -G0. The increase in PGE2, thromboxane B2, and TGF-β1 was inhibited by COX-2-specific inhibitor CAY10404 but not by COX-1-specific inhibitor SC-560. These results demonstrate a novel role of ApoL1 variants in the regulation of monocyte differentiation and eicosanoid metabolism, which could modify the immune response and promote inflammatory signaling within the local targeted organs and tissues including the kidney.

Adaptation of the Cardiac Myofiber Orientations Through Deformation: Computational Analysis of the Myocardial Structure

2008 ◽  
Author(s):  
Wilco Kroon ◽  
Tammo Delhaas ◽  
Peter Bovendeerd ◽  
Theo Arts
Keyword(s):  
Oxygen Consumption ◽  
Mechanical Loading ◽  
Computational Analysis ◽  
Mechanical Load ◽  
Mechanical Factors ◽  
Myocardial Structure

The distribution of mechanical load throughout the wall is very sensitive to the myofiber orientation [1]. Yet, heterogeneity myofiber shortening, metabolism as well as oxygen consumption is limited, indicating heterogeneity in mechanical load is limited [2,4]. This suggests that mechanical loading is able to control the myofiber direction. However, the relation between mechanical loading and the myocardial structure remains unclear. Understanding this relation may be useful to gain additional knowledge about the role of mechanical factors in (patho-)physiology of the myocardial structure.

Role of NF-κB in TNF-α-induced COX-2 Expression in Synovial Fibroblasts from Human TMJ

2007 ◽  
Vol 86 (4) ◽  
pp. 363-367 ◽  
Author(s):  
J. Ke ◽  
X. Long ◽  
Y. Liu ◽  
Y.F. Zhang ◽  
J. Li ◽  
...  
Keyword(s):  
Synovial Fibroblasts ◽  
Nuclear Factor Κb ◽  
Mobility Shift ◽  
Tnf Α ◽  
Cox 2 ◽  
Mobility Shift Assay ◽  
Pre Treatment ◽  
Factor Α ◽  
Necrosis Factor

In the temporomandibular joint (TMJ) synovium, cyclo-oxygenase-2 (COX-2) expression has been believed to be directly related to joint pain and synovitis. Here we investigated the role of Nuclear Factor κB (NF-κB) in the regulation of COX-2 expression in synovial fibroblasts from human TMJ induced by tumor necrosis factor-α (TNF-α). By reverse-transcriptase/polymerase chain-reaction (RT-PCR) and Western blotting analysis, TNF-α induced a dose- and time-dependent increase in COX-2 expression. Electrophoretic mobility shift assay (EMSA) revealed that transient NF-κB activation in the COX-2 promoter was triggered by TNF-α. In parallel with transient NF-κB activation, the rapid translocation of NF-κB, particularly the p65 subunit, from the cytoplasm into the nucleus was demonstrated. Pre-treatment with pyrolidine dithiocarbamate (PDTC), one of the NF-κB inhibitors, prevented binding to the COX-2 promoter and expression of COX-2 protein in response to TNF-α. These findings indicate that activation of NF-κB is responsible for TNF-α-induced COX-2 expression in synovial fibroblasts from the TMJ.

Lower-limb veins are thicker and vascular reactivity is decreased in a rat PCOS model: concomitant vitamin D3 treatment partially prevents these changes

2014 ◽  
Vol 307 (6) ◽  
pp. H848-H857 ◽  
Author(s):  
Szabolcs Várbíró ◽  
Levente Sára ◽  
Péter Antal ◽  
Anna Monori-Kiss ◽  
Anna-Mária Tőkés ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Mechanical Load ◽  
Polycystic Ovary ◽  
Varicose Veins ◽  
Saphenous Veins ◽  
Female Wistar Rats ◽  
Cox 2 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Polycystic ovary syndrome (PCOS) causes vascular damage to arteries; however, there are no data for its effect on veins. Our aim was to clarify the effects of dihydrotestosterone (DHT)-induced PCOS both on venous biomechanics and on pharmacological reactivity in a rat model and to test the possible modulatory role of vitamin D3 (vitD). PCOS was induced in female Wistar rats by DHT treatment (83 μg/day, subcutaneous pellet). After 10 wk, the venous biomechanics, norepinephrine (NE)-induced contractility, and acetylcholine-induced relaxation were tested in saphenous veins from control animals and from animals treated with DHT or DHT with vitD using pressure angiography. Additionally, the expression levels of endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX-2) were measured using immunohistochemistry. Increased diameter, wall thickness, and distensibility as well as decreased vasoconstriction were detected after the DHT treatment. Concomitant vitD treatment lowered the mechanical load on the veins, reduced distensibility, and resulted in vessels that were more relaxed. Although there was no difference in the endothelial dilation tested using acetylcholine (ACh), the blocking effect of NG-nitro-l-arginine methyl ester (l-NAME) was lower and was accompanied by lower COX-2 expression in the endothelium after the DHT treatment. Supplementation with vitD prevented these alterations. eNOS expression did not differ among the three groups. We conclude that the hyperandrogenic state resulted in thicker vein walls. These veins showed early remodeling and altered vasorelaxant mechanisms similar to those of varicose veins. Alterations caused by the chronic DHT treatment were prevented partially by concomitant vitD administration.

In Vitro Evidence of the Role of COX-2 in Attenuating Gastric Inflammation and Promoting Gastric Carcinogenesis

2002 ◽  
Vol 21 (2) ◽  
pp. 12 ◽  
Author(s):  
Ki-Baik Hahm ◽  
Ho-Yeong Lim ◽  
Seonghyang Sohn ◽  
Hyuk-Jae Kwon ◽  
Ki-Myung Lee ◽  
...  
Keyword(s):  
Gastric Carcinogenesis ◽  
Cox 2

The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

2020 ◽  
Vol 27 ◽  
Author(s):  
Rana A. Alaaeddine ◽  
Perihan A. Elzahhar ◽  
Ibrahim AlZaim ◽  
Wassim Abou-Kheir ◽  
Ahmed S.F. Belal ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Biological Effects ◽  
Arachidonic Acid Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Targets ◽  
Design And Synthesis ◽  
Early Results ◽  
Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

The Role of Synovial Fibroblasts in Mediating Joint Destruction in Rheumatoid Arthritis

2005 ◽  
Vol 11 (5) ◽  
pp. 563-568 ◽  
Author(s):  
Ingmar Meinecke ◽  
Edita Rutkauskaite ◽  
Steffen Gay ◽  
Thomas Pap
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Synovial Fibroblasts

scholarly journals Proteomic Analysis of Synovial Fibroblasts and Articular Chondrocytes Co-Cultures Reveals Valuable VIP-Modulated Inflammatory and Degradative Proteins in Osteoarthritis

2021 ◽  
Vol 22 (12) ◽  
pp. 6441
Author(s):  
Selene Pérez-García ◽  
Valentina Calamia ◽  
Tamara Hermida-Gómez ◽  
Irene Gutiérrez-Cañas ◽  
Mar Carrión ◽  
...  
Keyword(s):  
Isotope Labeling ◽  
Articular Chondrocytes ◽  
Synovial Fibroblasts ◽  
Immune Mediators ◽  
Cartilage Extracellular Matrix ◽  
Fibronectin Fragments ◽  
Ecm Degradation ◽  
Key Events ◽  
First Time

Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.

scholarly journals The role of 25-hydroxyvitamin-D3 and vitamin D receptor gene in human periodontal ligament fibroblasts as response to orthodontic compressive strain: an in vitro study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Erika Calvano Küchler ◽  
Agnes Schröder ◽  
Vinicius Broska Teodoro ◽  
Ute Nazet ◽  
Rafaela Scariot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Single Nucleotide Polymorphisms ◽  
Periodontal Ligament ◽  
Compressive Strain ◽  
Nucleotide Polymorphisms ◽  
Periodontal Ligament Fibroblasts ◽  
Single Nucleotide ◽  
Cox 2

Abstract Background This study aimed to investigate, if different physiological concentrations of vitamin D (25(OH)D3) and single nucleotide polymorphisms in vitamin D receptor (VDR) gene have an impact on gene expression in human periodontal ligament (hPDL) fibroblasts induced by simulated orthodontic compressive strain. Methods A pool of hPDL fibroblasts was treated in absence or presence of 25(OH)D3 in 3 different concentrations (10, 40 and 60 ng/ml). In order to evaluate the role of single nucleotide polymorphisms in the VDR gene, hPDL fibroblasts from 9 patients were used and treated in absence or presence of 40 ng/ml 25(OH)D3. Each experiment was performed with and without simulated orthodontic compressive strain. Real-time PCR was used for gene expression and allelic discrimination analysis. Relative expression of dehydrocholesterol reductase (DHCR7), Sec23 homolog A, amidohydrolase domain containing 1 (AMDHD1), vitamin D 25-hydroxylase (CYP2R1), Hydroxyvitamin D-1-α hydroxylase, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2) and interleukin-6 (IL6) was assessed. Three single nucleotide polymorphisms in VDR were genotyped. Parametric or non-parametric tests were used with an alpha of 5%. Results RANKL, RANKL:OPG ratio, COX-2, IL-6, DHCR7, CYP2R1 and AMDHD1 were differentially expressed during simulated orthodontic compressive strain (p < 0.05). The RANKL:OPG ratio was downregulated by all concentrations (10 ng/ml, 40 ng/ml and 60 ng/ml) of 25(OH)D3 (mean = 0.96 ± 0.68, mean = 1.61 ± 0.66 and mean = 1.86 ± 0.78, respectively) in comparison to the control (mean 2.58 ± 1.16) (p < 0.05). CYP2R1 gene expression was statistically modulated by the different 25(OH)D3 concentrations applied (p = 0.008). Samples from individuals carrying the GG genotype in rs739837 presented lower VDR mRNA expression and samples from individuals carrying the CC genotype in rs7975232 presented higher VDR mRNA expression (p < 0.05). Conclusions Simulated orthodontic compressive strain and physiological concentrations of 25(OH)D3 seem to regulate the expression of orthodontic tooth movement and vitamin-D-related genes in periodontal ligament fibroblasts in the context of orthodontic compressive strain. Our study also suggests that single nucleotide polymorphisms in the VDR gene regulate VDR expression in periodontal ligament fibroblasts in the context of orthodontic compressive strain.

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