Defective Signal Transduction in Osteoarthritic Chondrocytes and Synovial Fibroblasts Should Become a Target for Drug Intervention

Proteolytic fragments of fibronectin can have catabolic effects on cartilage, menisci, and synovium. Previous studies have reported that Toll-like receptor (TLR) signaling pathways might be associated with joint inflammation and joint destruction. Platelet-rich plasma (PRP) is increasingly being used to treat a range of joint conditions; however, it has yet to be determined whether PRP influences fibronectin fragment (FN-f) procatabolic activity and TLRs. In this study, human primary culture cells were treated with 30 kDa FN-f with/without PRP co-incubation, and then analyzed using real-time PCR to determine gene expression levels in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts. Protein levels were evaluated by Western immunoblotting. This study observed an increase in the protein expression of matrix metalloproteinases (MMPs), Toll-like receptor 2 (TLR2), nitric oxide synthase 2 (NOS2), prostaglandin-endoperoxide synthase (PTGS2), and cyclooxygenase 2 (COX2) in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts following insult with 30 kDa FN-f. Upregulation of these genes was significantly attenuated by PRP treatment. TLR2 and matrix metalloproteinase 13 (MMP-13) were also significantly attenuated by cotreatment with 30 kDa FN-f + PRP + TLR2 inhibitor. PRP treatment was shown to attenuate the 30 kDa FN-f-induced MMP-13 expression associated with the decreased expression of TLR2 in osteoarthritic chondrocytes and synovial fibroblasts. PRP treatment was also shown to attenuate procatabolic activity associated with MMP-13 expression via the TLR2 signaling pathway.

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FRI0044 IL-1 dependent SYNDECAN-4 signal transduction is mediated by its heparan sulfate side chains in RA synovial fibroblasts

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2012-eular.2501 ◽

2013 ◽

Vol 71 (Suppl 3) ◽

pp. 324.1-324

Author(s):

L. Godmann ◽

A. Stratis ◽

C. Cromme ◽

E. Frank Echtermeyer ◽

T. Pap ◽

...

Keyword(s):

Signal Transduction ◽

Heparan Sulfate ◽

Synovial Fibroblasts ◽

Side Chains

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Interleukin-1β switches electrophysiological states of synovial fibroblasts

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.5.r1822 ◽

1997 ◽

Vol 273 (5) ◽

pp. R1822-R1828 ◽

Cited By ~ 3

Author(s):

Oleg V. Kolomytkin ◽

Andrew A. Marino ◽

Kalia K. Sadasivan ◽

Robert E. Wolf ◽

James A. Albright

Keyword(s):

Signal Transduction ◽

Cell Membrane ◽

Synergistic Effect ◽

Gap Junction ◽

Synovial Fibroblasts ◽

The State ◽

Interleukin 1Β ◽

Junction Resistance ◽

Mediator System

The role of electrophysiological events in signal transduction of interleukin-1β (IL-1β) was investigated in rabbit synovial fibroblasts using the perforated-patch method. Aggregated synovial fibroblasts occurred in two different electrophysiological states having membrane potentials ( V m) of −63 ± 4 ( n = 71) and −27 ± 10 mV ( n = 55) (high and low V m, respectively). IL-1β affected the cells with high V m; it switched the state of the cell from high to low V m. This effect was strongly dependent on the external potential applied to the cell membrane. Low V m(−30 mV) alone without IL-1β did not switch the state of the cells. Thus a synergistic effect involving the cytokine and cell V m in switching the electrophysiological state of the cell was shown, indicating that electrophysiological changes are involved in signal transduction. Gap junctions between aggregated cells were necessary for the cells to have a high V m and to respond to IL-1β. Gap junction resistance between adjacent cells was estimated as 300 ± 100 MΩ. Our findings suggest that the electrophysiological behavior of synovial fibroblasts is tightly connected to a signaling or intracellular mediator system that is triggered by IL-1β.

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Phagocytosis mediated by Yersinia invasin induces collagenase-1 expression in rabbit synovial fibroblasts through a proinflammatory cascade

Journal of Cell Science ◽

10.1242/jcs.114.18.3333 ◽

2001 ◽

Vol 114 (18) ◽

pp. 3333-3343

Author(s):

Erica Werner ◽

Farrah Kheradmand ◽

Ralph R. Isberg ◽

Zena Werb

Keyword(s):

Signal Transduction ◽

Cellular Response ◽

Surface Protein ◽

Synovial Fibroblasts ◽

Small Gtpase ◽

Tnf Α ◽

Interleukin 1Α ◽

Factor Α ◽

Blocking Antibodies ◽

Necrosis Factor

We show that the interaction of the Yersinia surface protein, invasin, with rabbit synovial fibroblasts mediates bead phagocytosis and induces expression of interleukin 1α (IL-1α), tumor necrosis factor-α (TNF-α) and MMP-1/collagenase-1 (CL-1). Presentation of invasin as a ligand on the surface of 4.5 μm beads induced phagocytosis and increased CL-1 expression 20-fold after 24 hours. By contrast, presentation of invasin as a spreading substrate did not induce CL-1 expression. CL-1 induction following phagocytosis of invasin-coated beads was mediated by a mechanism dependent on high-affinity binding to β1 integrins and the function of the small GTPase RhoA. Expression of a function-perturbing mutant, RhoAN19, abrogated bead-induced CL-1 expression. RhoA activation coupled bead phagocytosis with signal transduction because expression of constitutively active mutant RhoV14 was sufficient to trigger CL-1 expression. The signal-transduction cascade elicited by bead phagocytosis triggered NFκB activation, stimulating a proinflammatory cellular response with transient increases in TNF-α production that peaked at 2 hours and induction of IL-1α that was sustained for at least 10 hours. Inhibition of IL-1α function by blocking antibodies or IL-1 receptor antagonist showed that IL-1α is the autocrine intermediary for subsequent CL-1 induction.

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Integration of the NF-κB and mitogen-activated protein kinase/AP-1 pathways at the Collagenase-1 promoter: Divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts

Cytokine ◽

10.1006/cyto.2000.0743 ◽

2000 ◽

Vol 12 (10) ◽

pp. 1469-1479 ◽

Cited By ~ 106

Author(s):

Aaron Barchowsky ◽

Davor Frleta ◽

Matthew P Vincenti

Keyword(s):

Signal Transduction ◽

Protein Kinase ◽

Synovial Fibroblasts ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Dependent Signal ◽

Promoter Divergence

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Effect of TLR4/MyD88 Signaling Pathway on Expression of IL-1βand TNF-αin Synovial Fibroblasts from Temporomandibular Joint Exposed to Lipopolysaccharide

Mediators of Inflammation ◽

10.1155/2015/329405 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 16

Author(s):

Xuefen Lin ◽

Jingjing Kong ◽

Qingting Wu ◽

Yingying Yang ◽

Ping Ji

Keyword(s):

Signal Transduction ◽

Temporomandibular Joint ◽

Interleukin 1 ◽

Signal Transduction Pathway ◽

Synovial Fibroblasts ◽

Signal Pathways ◽

Transduction Pathway ◽

Inhibitory Peptide ◽

Surface Receptors ◽

Protein Levels

Accumulating evidence from previous studies suggested that interleukin-1 (IL-1β) and tumor necrosis factor-α(TNF-α) play an important role in pathogenesis of temporomandibular disorders (TMD). However, the cell surface receptors and the intracellular signal pathways leading to these cytokines expression are not fully understood. In the current study, we investigated the roles of Toll-like receptor 4 (TLR4) and its adaptor myeloid differentiation factor 88 (MyD88) in the expression of IL-1βand TNF-αin synovial fibroblasts (SFs) separated from rat temporomandibular joint (TMJ) with lipopolysaccharide (LPS) stimulation. The results showed that treatment with LPS could increase TLR4, MyD88, IL-1β, and TNF-αexpression at both mRNA and protein levels. In addition, increased expression of IL-1βand TNF-αcould be blocked by treatment with TAK-242, a blocker of TLR4 signaling, and also by MyD88 inhibitory peptide (MIP). These findings suggested that maybe TLR4/MyD88 signal transduction pathway participates in enhanced expression of IL-1 and TNF-αin patients with TMD. The activation of TLR4/MyD88 signal transduction pathway which results in production of proinflammatory factors may play a role in the pathogenesis of TMD.

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Ultrastructural aspects of olfactory signal transduction and its development

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010016844x ◽

1994 ◽

Vol 52 ◽

pp. 142-143

Author(s):

Bert Ph. M. Menco

Keyword(s):

Signal Transduction ◽

Olfactory Receptor ◽

Receptor Cell ◽

Freeze Substitution ◽

Luminal Surface ◽

Tissue Sections ◽

Olfactory Receptor Cells ◽

Receptor Cells ◽

Olfactory Signal ◽

Odor Molecule

Vertebrate olfactory receptor cells are specialized neurons that have numerous long tapering cilia. The distal parts of these cilia line the interface between the external odorous environment and the luminal surface of the olfactory epithelium. The length and number of these cilia results in a large surface area that presumably increases the chance that an odor molecule will meet a receptor cell. Advanced methods of cryoprepration and immuno-gold labeling were particularly useful to preserve the delicate ultrastructural and immunocytochemical features of olfactory cilia required for localization of molecules involved in olfactory signal-transduction. We subjected olfactory tissues to freeze-substitution in acetone (unfixed tissues) or methanol (fixed tissues) followed by low temperature embedding in Lowicryl K11M for that purpose. Tissue sections were immunoreacted with several antibodies against proteins that are presumably important in olfactory signal-transduction.

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