Native and fragmented fibronectin oppositely modulate monocyte secretion of MMP-9

Marom, Barak; Rahat, Michal A.; Lahat, Nitza; Weiss-Cerem, Lea; Kinarty, Amalia; Bitterman, Haim

doi:10.1189/jlb.0506328

Cited by 42 publications

(36 citation statements)

References 44 publications

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“…Fibronectin is an ECM glycoprotein that is produced by multiple cell types (including macrophages) and is a known in vitro substrate for MMP-9. In the wt LV infarct extracts, full-length fibronectin as well as fibronectin fragments were at lower levels in the MMP-9 null group compared to wt, in agreement with the results of Marom et al [15] The fact that full length fibronectin was higher in the wt than the null supports previous studies that show fibronectin matricryptic fragments in the post-MI LV can trigger a feedback mechanism to induce fibronectin expression. [26] Tenascin-C is a known MMP-9 ECM substrate that often co-localizes with MMPs at sites of active remodeling and has been previously shown to upregulate MMP-9 expression.…”

Section: Discussionsupporting

confidence: 82%

“…Third, the global proteomic effect of MMP-9 deletion was catalogued for the infarct region, which provides direction for MMP-9 targeted therapeutic strategies. We found differences in levels of previously known in vitro MMP-9 substrates (fibronectin, tenascin-C, galectin-3, and serpina 1d) as well as in proteins that may be indirectly regulated by MMP-9 (BASP-1, desmin, and prohibitin-2); [14][15][16][17] and proteins that may be negatively regulated by MMP-9 (thrombospondin-1). [18] Since MMP-9 expression is strongly induced post-MI and absence of MMP-9 attenuates the degree of LV remodeling, [8] MMP-9 inhibition has been proposed as a possible therapy for the post-MI patient.…”

Section: Discussionmentioning

confidence: 87%

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Proteomic analysis identifies in vivo candidate matrix metalloproteinase‐9 substrates in the left ventricle post‐myocardial infarction

Zamilpa¹,

Lopez²,

Chiao³

et al. 2010

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MMP-9 deletion has been shown to improve remodeling of the left ventricle (LV) post-myocardial infarction (MI), but the mechanisms to explain this improvement have not been fully elucidated. MMP-9 has a broad range of in vitro substrates, but relevant in vivo substrates are incompletely defined. Accordingly, we evaluated the infarct regions of wild-type (wt) and MMP-9 null (null) mice using a proteomic strategy. Wt and null groups showed similar infarct sizes (48±3 in wt and 45±3% in null), indicating that both groups received an equal injury stimulus. LV infarct tissue was homogenized and analyzed by two-dimensional gel electrophoresis and mass spectrometry. Of 31 spot intensity differences, the intensities of 9 spots were higher and 22 spots were lower in null mice compared to wt (all p<0.05). Several extracellular matrix (ECM) proteins were identified in these spots by mass spectrometry, including fibronectin, tenascin-C, thrombospondin-1, and laminin. Fibronectin was observed on the gels at a lower than expected molecular weight in the wt group, which suggested substrate cleavage, and the lower molecular weight spot was observed at lower intensity in the MMP-9 null group, which suggested cleavage by MMP-9. Immunoblotting confirmed the presence of fibronectin cleavage products in the wt samples and lower levels in the absence of MMP-9. In conclusion, examining infarct tissue from wt and MMP-9 null mice by proteomic analysis provides a powerful and unique method to identify in vivo candidate MMP substrates.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 87%

Proteomic analysis identifies in vivo candidate matrix metalloproteinase‐9 substrates in the left ventricle post‐myocardial infarction

Zamilpa¹,

Lopez²,

Chiao³

et al. 2010

Proteomics Clinical Apps

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“…However, when an imbalance occurs, degradation products might trigger inflammation. For instance, fibronectin fragments alleviate metalloproteinase (MMP) inhibition and so promote monocyte migration in vitro [77]. This certainly facilitates their recruitment into the inflamed region.…”

Section: The Origin Of Inflammation In Intervertebral Discmentioning

confidence: 99%

Inflammation in intervertebral disc degeneration and regeneration

Molinos

Almeida

Caldeira

et al. 2015

J. R. Soc. Interface.

336

256

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Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overview of IVD regenerative therapies that target key inflammatory players.

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“…Here we demonstrate that MMP-9 is also induced in human monocytes by fibronectin peptides, suggesting that elevated levels of these peptides could accumulate locally, at least in part as a consequence of different activating loops, and then regulate several functions of target cells such as macrophages and HSC present in inflamed sites. This idea is also supported by the fact that fibronectin fragments antagonize the inhibitory effect of native fibronectin on MMP-9 production by monocytes (Marom et al, 2007).…”

Section: Discussionmentioning

confidence: 90%

Fibronectin Peptides as Potential Regulators of Hepatic Fibrosis Through Apoptosis of Hepatic Stellate Cells

Mòdol

Brice

Galarreta

et al. 2014

Journal Cellular Physiology

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The turnover of extracellular matrix (ECM) components can generate signals that regulate several cellular functions such as proliferation, differentiation, and apoptosis. During liver injury, matrix metalloproteases (MMPs) production is enhanced and increased levels of peptides derived from extracellular matrix proteins can be generated. Synthetic peptides with sequences present in extracellular matrix proteins were previously found to induce both stimulating and apoptotic effects on several cell types including the inflammatory cells monocytes/macrophages. Therefore, in inflammatory liver diseases, locally accumulated peptides could be also important in regulating hepatic fibrosis by inducing apoptosis of hepatic stellate cells (HSC), the primary cellular source of extracellular matrix components. Here, we describe the apoptotic effect of fibronectin peptides on the cell line of human hepatic stellate cells LX-2 based on oligonucleosomal DNA fragmentation, caspase-3 and -9 activation, Bcl-2 depletion, and accumulation of Bax protein. We also found that these peptides trigger the activation of Src kinase, which in turn mediated the increase of JNK and p38 activities. By the use of specific inhibitors we demonstrated the involvement of Src, JNK, and p38 in apoptosis induced by fibronectin peptides on HSC. Moreover, fibronectin peptides increased iNOS expression in human HSC, and specific inhibition of iNOS significantly reduced the sustained activity of JNK and the programmed cell death caused by these peptides. Finally, the possible regulatory effect of fibronectin peptides in liver fibrosis was further supported by the ability of these peptides to induce metalloprotease-9 (MMP-9) expression in human monocytes.

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Native and fragmented fibronectin oppositely modulate monocyte secretion of MMP-9

Cited by 42 publications

References 44 publications

Proteomic analysis identifies in vivo candidate matrix metalloproteinase‐9 substrates in the left ventricle post‐myocardial infarction

Proteomic analysis identifies in vivo candidate matrix metalloproteinase‐9 substrates in the left ventricle post‐myocardial infarction

Inflammation in intervertebral disc degeneration and regeneration

Fibronectin Peptides as Potential Regulators of Hepatic Fibrosis Through Apoptosis of Hepatic Stellate Cells

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