Antisense oligonucleotides to the integrin receptor subunit alpha5 decrease fibronectin fragment mediated cartilage chondrolysis

Homandberg, Gene A.; Costa, Valéria Catelli Infantozzi; Ummadi, V.; Pichika, Rajeswari

doi:10.1053/joca.2002.0524

Cited by 40 publications

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References 46 publications

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“…Antibodies against ␣5␤1 have been shown to block the effect of FN on phosphorylation of p70 S6K, a downstream signal of mTOR (9). Antisense oligonucleotides to the integrin receptor subunit ␣5 decreased FN fragment-mediated cartilage chondrolysis (49). Chondrosarcoma-derived chondrocytic cell adhesion to FN was abolished by a blocking antibody against ␣5␤1 integrin, but not by one against anti-␣v␤3 integrin, suggesting the specificity of this integrin in mediating many FN functions (50).…”

Section: Discussionmentioning

confidence: 99%

Fibronectin Increases Matrix Metalloproteinase 9 Expression through Activation of c-Fos via Extracellular-regulated Kinase and Phosphatidylinositol 3-Kinase Pathways in Human Lung Carcinoma Cells

Han

Ritzenthaler

Sitaraman

et al. 2006

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) 2 are a family of zinc enzymes responsible for degradation of extracellular matrix components including basement membrane collagen, interstitial collagens, fibronectin (FN), and various proteoglycans during normal remodeling and repair processes (1, 2). The potent proteolytic activities of MMPs are mainly regulated by the concomitant expression of specific tissue inhibitors of matrix metalloproteinases (3). Excessive or inappropriate expression of MMPs may contribute to the pathogenesis of tissue destructive processes in a wide variety of diseases including lung disorders like bronchial asthma, chronic obstructive pulmonary disease, acute lung injury, pulmonary hypertension, and interstitial lung diseases (2, 4). In addition, MMPs have been implicated in the progression and metastases of different tumors including lung cancer (see later in text).One member of the MMP family is the 92-kDa type IV collagenase MMP-9. The MMP-9 gene is encoded on chromosome 20 and its expression is under the control of a 2.2-kb upstream regulatory sequence harboring binding sites for AP-1, NF-B, Sp1, and others (5). MMP-9 expression is increased in malignant cancers when compared with benign tumors and non-invasive ones, and there is compelling in vitro and in vivo evidence for a role of MMP-9 in tumor invasion and angiogenesis (6, 7). Its dramatic overexpression in cancer and various inflammatory conditions suggest that this protease is a potential target for the development of novel therapeutic interventions (8).Because of its perceived importance, our research focuses on the factors that increase MMP-9 expression in the lung. Our search led us to FN, a matrix glycoprotein highly expressed in tobacco-related lung disease that has been shown to stimulate lung carcinoma cell growth through several mechanisms (9 -11). Cell adhesion to FN results in MMP secretion in normal and tumor cell systems (12)(13)(14). These studies suggest that tumor cell interactions with FN might lead to MMP-9 expression thereby promoting cancer cell migration, invasion, and related processes. However, the mechanisms by which FN stim-* This work was supported by American Lung Association Bioresearch Grant RG-10215N (to S. W. H.) and by a Merit Review Grant from the Department of Veterans Affairs (to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

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Section: Discussionmentioning

confidence: 99%

Fibronectin Increases Matrix Metalloproteinase 9 Expression through Activation of c-Fos via Extracellular-regulated Kinase and Phosphatidylinositol 3-Kinase Pathways in Human Lung Carcinoma Cells

Han

Ritzenthaler

Sitaraman

et al. 2006

Journal of Biological Chemistry

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“…As shown in Fig. 4A, Western blot analysis showed an increase in the accumulated MMP-13 protein present in the conditioned medium of chondrocyte cultures treated with purified HA 6 or HA oligo as compared with control, untreated cells. The data were obtained from chondrocytes isolated from three different human donors.…”

Section: Resultsmentioning

confidence: 63%

“…Like the bovine chondrocytes, activation of the media samples with APMA resulted in the formation of mature MMP-13 at 50 kDa, again demonstrating that the MMP that is released in human chondrocyte cultures is also predominately the proenzyme form. In summary, HA 6 or HA oligo induce the expression of MMP-13 mRNA, increase MMP-13 protein, and enhance MMP-13-related enzymatic activity.…”

Section: Resultsmentioning

confidence: 90%

“…Again, there is significant activity in the media of control, untreated cells (Fig. 4B, lanes 1 and 4) but substantial up-regulation upon treatment of the chondrocytes for 24 h with purified HA 6 . Interestingly, treatment of the human chondrocytes with HA 4 , oligosaccharides that do not interact efficiently with CD44, did not affect a stimulation of caseinolytic activity.…”

Section: Resultsmentioning

confidence: 91%

“…For signaling inhibition assays, bovine chondrocytes were pretreated with inhibitors of NFB (1 nM helenalin; Calbiochem), p38 MAP kinase (5 nM SB203580; Calbiochem) or MAP kinase kinase (MEK) (10 nM PD98059; Calbiochem) for 1 h and then treated with 250 g/ml HA oligo for 24 h in the presence or absence of each inhibitor. In some recovery experiments, cultures of COS-7 cells were washed excessively with DMEM after a 12-h treatment with 250 g/ml HA 6 and then incubated in fresh media with or without 500 g/ml high molecular mass HA (HMW-HA) (ϳ5.0 ϫ 10 5-7.3 ϫ 10 5 Da; HYAL-GAN, Sanofi-Synthelabo Inc., New York, NY).…”

Section: Materials-antibodiesmentioning

confidence: 99%

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Hyaluronan Oligosaccharides Induce Matrix Metalloproteinase 13 via Transcriptional Activation of NFκB and p38 MAP Kinase in Articular Chondrocytes

Ohno

Knudson

et al. 2006

Journal of Biological Chemistry

114

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Hyaluronan exerts a variety of biological effects on cells including changes in cell migration, proliferation, and matrix metabolism. However, the signaling pathways associated with the action of hyaluronan on cells have not been clearly defined. In some cells, signaling is induced by the loss of cell-hyaluronan interactions. The goal of this study was to use hyaluronan oligosaccharides as a molecular tool to explore the effects of changes in cell-hyaluronan interactions and determine the underlying molecular events that become activated. In this study, hyaluronan oligosaccharides induced the loss of extracellular matrix proteoglycan and collagen from cultured slices of normal adult human articular cartilage. This loss was coincident with an increased expression of matrix metalloproteinase (MMP)-13. MMP-13 expression was also induced in articular chondrocytes by hyaluronan (HA) hexasaccharides but not by HA tetrasaccharides nor high molecular weight hyaluronan. MMP-13 promoterreporter constructs in CD44-null COS-7 cells revealed that both CD44-dependent and CD44-independent events mediate the induction of MMP-13 by hyaluronan oligosaccharides. Electromobility gel shift assays demonstrated the activation of chondrocyte NFB by hyaluronan oligosaccharides. NFB activation was also documented in C-28/I2 immortalized human chondrocytes by luciferase promoter assays and phosphorylation of IKK-␣/␤. The link between activation of NFB and MMP-13 induction by HA oligosaccharides was further confirmed through the use of the NFB inhibitor helenalin. Inhibition of MAP kinases also demonstrated the involvement of p38 MAP kinase in the hyaluronan oligosaccharide induction of MMP-13. Our findings suggest that hyaluronan-CD44 interactions affect matrix metabolism via activation of NFB and p38 MAP kinase.In many tissues cell-matrix interactions serve to regulate cellular homeostasis (1, 2). Interference with these associations typically signal cells to initiate matrix repair, cell proliferation, or even cell migration. Such interactions are especially important in tissues such as articular cartilage, a tissue rich in extracellular matrix but with limited vascular access for systemic control of homeostasis. Chondrocytes are thus highly dependent on cell-matrix interactions as a primary means to "sense" changes in the extracellular environment (3). Most investigations in this area focus on cell signaling induced through the interaction of integrin receptors with collagens, fibronectin, laminin, matrilins, etc.(3-7). However, cell-matrix interactions involving hyaluronan (HA), 2 once thought to be predominately structural in nature, are now beginning to receive increasing attention as initiators of cell signaling.HA is a high molecular weight polysaccharide consisting of repeating disaccharide units glucuronic acid and N-acetylglucosamine (8). In cartilage and many other connective tissues, HA serves as a central filamentous scaffold to which proteoglycans such as aggrecan and link protein become bound (9). This complex matrix networ...

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Involvement of CD44 in induction of matrix metalloproteinases by a COOH‐terminal heparin‐binding fragment of fibronectin in human articular cartilage in culture

Yasuda

Poole

Shimizu

et al. 2003

Arthritis & Rheumatism

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Objective. To investigate the mechanism of induction of matrix metalloproteinases (MMPs) by a 40-kd COOH-terminal heparin-binding fibronectin fragment (HBFN-f) containing III12-14 and IIICS domains in human articular cartilage in culture.Methods. Human articular cartilage was removed from macroscopically normal femoral heads and cultured with HBFN-f. MMP secretion into conditioned media was analyzed by immunoblotting (MMPs 1 and 13) and by gelatin zymography (MMPs 2 and 9). Type II collagen cleavage by collagenase was monitored in culture by immunoassay. Involvement of specific peptidebinding domains in HBFN-f and the involvement of CD44 were assessed with synthetic peptides and an anti-CD44 antibody. Immunofluorescence histochemistry was performed using fluorescein isothiocyanateconjugated anti-CD44 antibody.Results. HBFN-f stimulated production of MMPs 1, 2, 9, and 13 in association with type II collagen cleavage by collagenase in human articular cartilage. Peptide V (WQPPRARI) of HBFN-f, which can bind cell surface heparan sulfate proteoglycan (HSPG), blocked MMP induction by HBFN-f, while the scrambled peptide V (RPQIPWAR) had no effect. Peptide CS-1 of 25 amino acids in IIICS of HBFN-f caused no significant effect. Treatment of cartilage with anti-CD44 antibody or HSPG resulted in significant inhibition of HBFN-fstimulated MMP production. Preincubation with peptide V blocked binding of the anti-CD44 antibody to chondrocytes in cartilage.Conclusion. Interaction of the peptide V sequence in HBFN-f with glycosaminoglycans, such as those in CD44, plays an important role in HBFN-f-stimulated MMP production in articular cartilage. Because CD44 is up-regulated in osteoarthritic and rheumatoid arthritic cartilage, the role of the interaction between CD44 and HBFN-f in these pathologies should be of relevance and should be studied further.The extracellular matrix of articular cartilage is composed mainly of proteoglycans and collagens, and its integrity provides the mechanical properties of cartilage (1). Progressive destruction of cartilage, which results from an imbalance between the anabolic and catabolic processes, is a common feature of rheumatoid arthritis (RA) and osteoarthritis (OA). Interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ have been shown to promote cartilage degradation by stimulating the production of matrix metalloproteinases (MMPs) (2).Fibronectin is a component of normal cartilage matrix (3). It consists primarily of 3 types of homologous repeating segments (designated I, II, and III). Fibronectin contains NH 2 -, gelatin-, cell-, and COOH-terminal heparin-binding domains. The central cell-binding region has an RGD sequence in domain III10, which is recognized by several cell surface integrin family members (4). Several sites in the heparin-binding domain that lie COOH-terminal to the central cell-binding domain also interact with the cell surface. Regions of domain III12-14 support cell attachment with varying affinities (5-7). The IIICS, or variable (V) region, contains the

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Antisense oligonucleotides to the integrin receptor subunit alpha5 decrease fibronectin fragment mediated cartilage chondrolysis

Abstract: These data implicate the alpha(5) integrin subunit in Fn-f mediated activities, consistent with a role for the alpha(5)beta(1) integrin in this pathway.

Cited by 40 publications

References 46 publications

Fibronectin Increases Matrix Metalloproteinase 9 Expression through Activation of c-Fos via Extracellular-regulated Kinase and Phosphatidylinositol 3-Kinase Pathways in Human Lung Carcinoma Cells

Fibronectin Increases Matrix Metalloproteinase 9 Expression through Activation of c-Fos via Extracellular-regulated Kinase and Phosphatidylinositol 3-Kinase Pathways in Human Lung Carcinoma Cells

Hyaluronan Oligosaccharides Induce Matrix Metalloproteinase 13 via Transcriptional Activation of NFκB and p38 MAP Kinase in Articular Chondrocytes

Involvement of CD44 in induction of matrix metalloproteinases by a COOH‐terminal heparin‐binding fragment of fibronectin in human articular cartilage in culture

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