NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments

Pulai, Judit I.; Chen, Hong; Im, Hee Jeong; Kumar, Sanjay; Hanning, Charles R.; Hegde, Priti S.; Loeser, Richard F.

doi:10.4049/jimmunol.174.9.5781

Cited by 196 publications

(180 citation statements)

References 38 publications

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“…Deletion from Ϫ1600 (Ϫ1600MMP-13) to Ϫ736 (Ϫ736MMP-13) upstream of the ATG of the MMP-13 promoter region shows no significant change in the basal promoter activity (Fig. 1A), consistent with our previous report with an immortalized chondrocyte cell line (30,32). Further deletion from Ϫ736 to Ϫ370 of the MMP-13 promoter (Ϫ370MMP-13) significantly reduces basal promoter activity (up to ϳ40% reduction).…”

Section: Identification Of An Elk-1 Response Element In the Distal Prsupporting

confidence: 80%

“…Human adult articular chondrocytes were transiently co-transfected with a construct (pCMV-IB␣M), expressing a dominant negative form of IB␣, and the MMP-13 promoter/luciferase reporter plasmid. Expression of IB␣M blocks endogenous NFB signaling by competitively binding to NFB and preventing the release of activated NFB (18,30,32). Our results showed that exogenous expression of IB␣M dramatically inhibited the bFGF-mediated stimulation of MMP-13 promoter activity (Fig.…”

Section: Bfgf-mediated Phosphorylation Of Elk-1 At Serine 383 Is Linksupporting

confidence: 56%

“…Transient Transfection by Nucleofection (Electroporation)-Nucleofection methods were optimized for use with human articular chondrocytes by minor modifications of the instructions for the Nucleofector TM kit (Amaxa Biosystems) that have been described previously (18,32). The Renilla vector (pRL-TK) was co-transfected as an internal control, and the luciferase activity representing promoter activity was measured using the Dual-Luciferase reporter assay system (Promega) and a lumi-nometer (Berthold).…”

Section: Methodsmentioning

confidence: 99%

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Basic Fibroblast Growth Factor Activates the MAPK and NFκB Pathways That Converge on Elk-1 to Control Production of Matrix Metalloproteinase-13 by Human Adult Articular Chondrocytes

Muddasani¹,

Norman

Ellman

et al. 2007

Journal of Biological Chemistry

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122

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The pathology of joint destruction is associated with elevated production of basic fibroblast growth factor (bFGF) and matrix metalloproteinase-13 (MMP-13). In osteoarthritic joint disease, expression of bFGF and MMP-13 in chondrocytes and their release into the synovial fluid are significantly increased. We have previously found that the capacity for cartilage repair in human adult articular chondrocytes is severely compromised by minimal exposure to bFGF because bFGF reduces responsiveness to bone morphogenetic protein-7 and insulin-like growth factor-1 and induces MMP-13 through protein kinase C␦-dependent activation of multiple mitogen-activated protein kinase (MAPK) signaling pathways. Here we show using biochemical and molecular approaches that transcription factor Elk-1, a direct downstream target of MAPK, is a critical transcriptional activator of of MMP-13 by bFGF in human articular chondrocytes. We also provide evidence that Elk-1 is a direct target of NFB and induces MMP-13 expression upon activation of the NFB signaling pathway. Taken together, our results suggest that elevated expression of MMP-13 occurs through Elk-1 activation of both MAPK and NFB signaling pathways, thus revealing a two-pronged biological mechanism by which bFGF controls the production of catabolic enzymes that are associated with excessive degradation of the cartilage matrix in degenerative joint diseases such as osteoarthritis.

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Section: Identification Of An Elk-1 Response Element In the Distal Prsupporting

confidence: 80%

Section: Bfgf-mediated Phosphorylation Of Elk-1 At Serine 383 Is Linksupporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Basic Fibroblast Growth Factor Activates the MAPK and NFκB Pathways That Converge on Elk-1 to Control Production of Matrix Metalloproteinase-13 by Human Adult Articular Chondrocytes

Muddasani¹,

Norman

Ellman

et al. 2007

Journal of Biological Chemistry

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122

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“…In many cell types such as chondrocytes (55), synovial cells (56), and monocytes (30,54), signals transduced via ␣5␤1 result in cell survival, proliferation, and cytokine and chemokine expression. We show herein that the engagement of ␣5␤1 by sCD40L on U937 cells is also functionally relevant, because it induces the activation of ERK signaling pathways and the association of ␣5␤1 with the Triton X-100-insoluble fraction.…”

Section: Discussionmentioning

confidence: 99%

CD40 Ligand Binds to α5β1 Integrin and Triggers Cell Signaling

Léveillé

Bouillon

Wen

et al. 2007

Journal of Biological Chemistry

110

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It was originally thought that the critical role of the CD40 ligand (CD40L) in normal and inflammatory immune responses was mainly mediated through its interaction with the classic receptor, CD40. However, data from CD40L ؊/؊ and CD40؊/؊ mice suggest that the CD40L-induced inflammatory immune response involves at least one other receptor. This hypothesis is supported by the fact that CD40L stabilizes arterial thrombi through an ␣IIb␤3-dependent mechanism. Here we provide evidence that soluble CD40L (sCD40L) binds to cells of the undifferentiated human monocytic U937 cell line in a CD40-and ␣IIb␤3-independent manner. Binding of sCD40L to U937 cells was inhibited by anti-CD40L monoclonal antibody 5C8, anti-␣5␤1 monoclonal antibody P1D6, and soluble ␣5␤1. The direct binding of sCD40L to purified ␣5␤1 was confirmed in a solid phase binding assay. Binding of sCD40L to ␣5␤1 was modulated by the form of ␣5␤1 expressed on the cell surface as the activation of ␣5␤1 by Mn 2؉ or dithiothreitol resulted in the loss of sCD40L binding. Moreover, sCD40L induced the translocation of ␣5␤1 to the Triton X-100-insoluble fraction of U937 cells, the rapid activation of the MAPK pathways ERK1/2, and interleukin-8 gene expression. The binding of sCD40L to CD40 on BJAB cells, an ␣5␤1-negative B cell line, and the resulting activation of ERK1/2 was not inhibited by soluble ␣5␤1, suggesting that sCD40L can bind concomitantly to both receptors. These results document the existence of novel CD40L-dependent pathways of physiological relevance for cells expressing multiple receptors (CD40, ␣5␤1, and ␣IIb␤3) for CD40L. (2). The expression of CD154 is inducible, and its expression on T cells is triggered primarily by T cell receptor signaling and is regulated by CD28-dependent and independent pathways (3) CD40L is stored in platelets and a subpopulation of T cells and rapidly translocates to the cell membrane following T cell and platelet activation (4, 5). A soluble form of biologically active CD40L trimer (sCD40L) is present in the supernatant of activated T cells (6) and platelets (7) and results from the proteolytic cleavage of the homotrimeric CD40L by a metalloproteinase (7).It was originally thought that CD40L had only one receptor, CD40, which is a type I transmembrane protein that is a member of the TNF receptor superfamily. CD40 is expressed on the surface of many immune and non-immune cells, including B lymphocytes, monocytes/macrophages, and dendritic cells, as well as platelets, epithelial, and endothelial cells (8). Most biological functions of CD40L have been attributed to its direct interaction with CD40. However, studies using CD40L Ϫ/Ϫ and CD40 Ϫ/Ϫ mice have suggested that CD40L may also bind to one or more other receptors (9). In support of this hypothesis, it has been elegantly demonstrated that sCD40L interacts with ␣IIb␤3 (GPIIb/IIIa), an integrin expressed on platelets (10), triggering outside-in signaling and inducing platelet activation and spreading (11). CD40L Ϫ/Ϫ mice exhibit increased bleeding time (12) and reduce...

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“…As discussed in the context of OBs, mechanical stimulation can activate NF-κB in chondrocytes [68]. Matrix protein fragments, including those from the major cartilage component collagen II, also depend on NF-κB to stimulate expression of MMPs, NO and inflammatory cytokines [69,70]. Since biologic agents that block either TNFα or IL-1β do not block OA progression [71,72], it is likely that other stimuli for NF-κB activation, in combination with non-cytokine transcriptional targets of NF-κB, cause significant cartilage destruction.…”

Section: Osteoarthritismentioning

confidence: 99%

Role of NF-κB in the skeleton

2010

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Since the discovery that deletion of the NF-κB subunits p50 and p52 causes osteopetrosis in mice, there has been considerable interest in the role of NF-κB signaling in bone. NF-κB controls the differentiation or activity of the major skeletal cell types -osteoclasts, osteoblasts, osteocytes and chondrocytes. However, with five NF-κB subunits and two distinct activation pathways, not all NF-κB signals lead to the same physiologic responses. In this review, we will describe the roles of various NF-κB proteins in basal bone homeostasis and disease states, and explore how NF-κB inhibition might be utilized therapeutically.

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NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments

Cited by 196 publications

References 38 publications

Basic Fibroblast Growth Factor Activates the MAPK and NFκB Pathways That Converge on Elk-1 to Control Production of Matrix Metalloproteinase-13 by Human Adult Articular Chondrocytes

Basic Fibroblast Growth Factor Activates the MAPK and NFκB Pathways That Converge on Elk-1 to Control Production of Matrix Metalloproteinase-13 by Human Adult Articular Chondrocytes

CD40 Ligand Binds to α5β1 Integrin and Triggers Cell Signaling

Role of NF-κB in the skeleton

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