Expression of matrix metalloproteinase 9 (96‐kd gelatinase B) in human rheumatoid arthritis

Ahrens, Diane; Koch, Alisa E.; Pope, Richard M.; Stein-Picarella, Monica; Niedbala, Michael J.

doi:10.1002/art.1780390919

Cited by 271 publications

(189 citation statements)

References 49 publications

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“…MMP-9 plays a critical role in the invasion of the synovial tissue, leading to cartilage destruction and bone erosion in RA (7,10,33,34). The importance of this enzyme in arthritis is highlighted by the finding that MMP-9-knockout mice display less severe antibodyinduced arthritis than do wild-type mice (10).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of this enzyme in arthritis is highlighted by the finding that MMP-9-knockout mice display less severe antibodyinduced arthritis than do wild-type mice (10). MMP-9 is implicated in the degradation of basement membrane collagen, synovial membrane neovascularization, transfer of endothelial and hemopoietic stem cells from a quiescent to a proliferative state, and promotion of leukocyte migration from the vascular compartment to sites of inflammation (7,(35)(36)(37). In the RA synovial joint, levels of leukocyte-derived MMP-9 are directly related to the degree of inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…MMP-9 is markedly elevated in the sera and joints of RA patients (7,17,18) and correlates positively with disease progression and severity (7,18). MMP-9-knockout mice show reduced severity of antibodyinduced arthritis (10).…”

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confidence: 99%

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Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Xue

March

Sambrook

2007

Arthritis & Rheumatism

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Objective. To investigate the in vitro effect of activated protein C (APC), a natural anticoagulant and novel antiinflammatory agent, on the regulation of the gelatinases matrix metalloproteinase 2 (MMP-2) and MMP-9.Methods. Synovial fibroblasts and peripheral blood monocytes isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and Mono Mac6 cells were used in this study. After treatment, cells and culture supernatants were collected for zymography, enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and Western blot analysis.Results. Fibroblasts and monocytes from RA patients produced substantially more MMP-9 than did those from OA patients; however, there was no difference in MMP-2 production. The addition of recombinant APC markedly reduced MMP-9 at the gene and protein levels. In contrast, APC up-regulated and activated MMP-2. Using a blocking antibody to the endothelial protein C receptor (EPCR), we showed that the inhibition of MMP-9 by APC was EPCR-dependent. Furthermore, APC directly suppressed the production of tumor necrosis factor (TNF) and the activation of NF-B and MAP kinase p38, and inhibitors of NF-B or p38 reduced the production of MMP-9, suggesting that APC inhibits MMP-9 by blocking TNF, NF-B, and p38. Thus, APC acts on MMP-9 by binding to EPCRs on the cell surface and, subsequently, inhibiting the intracellular activation of the proinflammatory signaling molecules NF-B and p38.Conclusion. APC appears to be the first physiologic agent to inhibit the production of proinflammatory MMP-9, yet increase antiinflammatory MMP-2 activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Xue

March

Sambrook

2007

Arthritis & Rheumatism

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“…As examples, these observations include increases in microvascular EC expression of MMP-1 during embryonic angiogenesis and vasculogenesis 47 and MMP-9 and -19 expression in ECs of the endothelium of rheumatoid arthritis synovium. 48,49 In some cases, EC expression of MMPs is differentially regulated spatially and/or temporally during the progression of a physiologic or pathologic condition, suggesting the involvement of the MMP at particular stages of the process. For instance, the cycle-specific pattern of expression of MMP-1, -2, -3, -9, TIMP-1 and TIMP-2 that was observed in blood vessels of the endometrium implies their involvement at different stages of the angiogenic process during the menstrual cycle.…”

Section: Endogenous Inhibitors Of Metalloproteinasesmentioning

confidence: 99%

Metalloproteinases and their inhibitors in tumor angiogenesis

Handsley

Edwards

2005

Intl Journal of Cancer

260

211

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Angiogenesis is the process by which new blood vessels are formed from preexisting vasculature. It is an essential feature of the female reproductive cycle, embryonic development and wound repair. Angiogenesis has also been identified as a causal or contributing factor in several pathologies, including cancer, where it is a rate-limiting step during tumor progression. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, in particular the gelatinases and membrane-type 1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, unmasking of cryptic biologically relevant sites in ECM components, modulation of angiogenic factors and production of endogenous angiogenic inhibitors. This review brings together what is currently known about the functions of the MMPs and the closely related ADAM (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families in angiogenesis and considers how this information might be useful in manipulation of the angiogenic process, with a view to constraining tumor progression. ' 2005 Wiley-Liss, Inc.Key words: metalloproteinase; tumor; angiogenesis; tissue inhibitor of metalloproteinases; protease; extracellular matrix Angiogenesis is an essential feature of several physiologic processes such as the developmental growth of organs, wound healing and the female reproductive cycle. 1 It is also particularly significant in cancer progression, being a crucial step in the transition of a tumor from a hyperplastic but contained in situ state to a malignant phenotype. 2,3 To allow its growth beyond a certain critical size, a solid avascular tumor must develop its own blood supply in order to meet its growing metabolic requirements. 1 Vascularization of a tumor also provides a route for dissemination of the tumor cells to different sites around the body.Although angiogenesis appears to be the primary form of tumor vascularization, the malignant cells of a tumor can gain access to a blood supply through other means, such as via tumor-induced vasculogenesis, in which bone marrow-derived precursor endothelial cells contribute to the formation of tumor vessels. 4,5 Vasculogenic mimicry is another form of vessel formation that has been reported in certain tumor types, such as aggressive human uveal melanomas, prostate and breast tumors. [6][7][8] In these cases, networks of tumor cell-lined vascular channels were identified within the tumors. Finally, vessel co-option, implemented by tumor cells as a temporary means of gaining access to a blood supply, involves the tumor cells growing around and thus co-opting existing host vessels to form an initially well-vascularized tumor. 9 This review will highlight new insigh...

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“…They are involved in the activation cascade of other proteinases relevant to RA, such as MMP-1, -2, -7, -8, -9, and -13 (34). Besides cartilage degradation, MMPs play a role in the migration of macrophages and neutrophils during RA (35,36) and can antagonize apoptosis of proliferating synovial cells, thereby exacerbating the inflammatory process (37). On the contrary, MMPs can suppress inflammation by degrading biologically active molecules such as cytokines, chemokines, and growth factor receptors (38 -42).…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis

Bilsen

Wagenaar-Hilbers

Grosfeld-Stulemeijer

et al. 2004

The Journal of Immunology

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Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.

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Expression of matrix metalloproteinase 9 (96‐kd gelatinase B) in human rheumatoid arthritis

Cited by 271 publications

References 49 publications

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Metalloproteinases and their inhibitors in tumor angiogenesis

Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis

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