References of "Werb, Z"
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See detailStromal regulation of vessel stability by MMP14 and TGFbeta.
Sounni, Nor Eddine ULg; Dehne, K.; van Kempen, L. et al

in Disease Models & Mechanisms (2010), 3

Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues involving matrix ... [more ▼]

Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues involving matrix metalloproteinase 14 (MMP14) and transforming growth factor beta (TGFbeta)1. Whereas plasma proteins rapidly extravasate out of vasculature in wildtype mice following acute damage, short-term treatment of mice in vivo with a broad-spectrum metalloproteinase inhibitor, neutralizing antibodies to TGFbeta1 or an ALK5 inhibitor significantly enhanced vessel leakage. In contrast, in a mouse model of age-related dermal fibrosis where MMP14 activity and TGFbeta bioavailability are chronically elevated, or in mice that ectopically express TGFbeta in epidermis, cutaneous vessels are resistant to acute leakage. Characteristic responses to tissue damage are reinstated if fibrotic mice are pre-treated with metalloproteinase inhibitors or TGFbeta signaling antagonists. Neoplastic tissues on the other hand are in a constant state of tissue damage and exhibit altered hemodynamics due to hyperleaky angiogenic vasculature. In two distinct transgenic mouse tumor models, inhibition of ALK5 further enhanced vascular leakage into interstitium and facilitated increased delivery of high molecular weight compounds into premalignant tissue and tumors. Taken together, these data define a central pathway involving MMP14 and TGFbeta that mediate vessel stability and vascular response to tissue injury. Antagonists of this pathway could be therapeutically exploited to improve delivery of therapeutics or molecular contrast agents into tissues where chronic damage or neoplastic disease limits their efficient delivery. [less ▲]

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See detailIncreased Inflammation Delays Wound Healing in Mice Deficient in Collagenase-2 (MMP-8)
Gutierrez-Fernandez, A.; Inada, M.; Balbin, M. et al

in FASEB Journal (2007), 21(10), 2580-91

Matrix metalloproteinases (MMPs) have been implicated in numerous tissue-remodeling processes. The finding that mice deficient in collagenase-2 (MMP-8) are more susceptible to develop skin cancer ... [more ▼]

Matrix metalloproteinases (MMPs) have been implicated in numerous tissue-remodeling processes. The finding that mice deficient in collagenase-2 (MMP-8) are more susceptible to develop skin cancer, prompted us to investigate the role of this protease in cutaneous wound healing. We have observed a significant delay in wound closure in MMP8-/- mice and an altered inflammatory response in their wounds, with a delay of neutrophil infiltration during the first days and a persistent inflammation at later time points. These changes were accompanied by alterations in the TGF-beta1 signaling pathway and by an apoptosis defect in MMP8-/- mice. The delay in wound healing observed in MMP8-/- mice was rescued by bone marrow transplantation from wild-type mice. Analysis of other MMPs showed that MMP8-/- mice had a significant increase in the expression of MMP-9, suggesting that both proteases might act coordinately in this process. This possibility was further supported by the novel finding that MMP-8 and MMP-9 form specific complexes in vivo. Taken together, these data indicate that MMP-8 participates in wound repair by contributing to the resolution of inflammation and open the possibility to develop new strategies for treating wound healing defects. [less ▲]

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See detailContribution of Host MMP-2 and MMP-9 to Promote Tumor Vascularization and Invasion of Malignant Keratinocytes
Masson, Véronique ULg; de la Ballina, L. R.; Munaut, Carine ULg et al

in FASEB Journal (2005), 19(2), 234-6

The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of growth factors ... [more ▼]

The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of growth factors, chemokines, and/or cytokines. Specific functions of individual MMPs as anti- or proangiogenic mediators remain to be elucidated. In the present study, we assessed the impact of single or combined MMP deficiencies in in vivo and in vitro models of angiogenesis (malignant keratinocyte transplantation and the aortic ring assay, respectively). MMP-9 was predominantly expressed by neutrophils in tumor transplants, whereas MMP-2 and MMP-3 were stromal. Neither the single deficiency of MMP-2, MMP-3, or MMP-9, nor the combined absence of MMP-9 and MMP-3 did impair tumor invasion and vascularization in vivo. However, there was a striking cooperative effect in double MMP-2:MMP-9-deficient mice as demonstrated by the absence of tumor vascularization and invasion. In contrast, the combined lack of MMP-2 and MMP-9 did not impair the in vitro capillary outgrowth from aortic rings. These results point to the importance of a cross talk between several host cells for the in vivo tumor promoting and angiogenic effects of MMP-2 and MMP-9. Our data demonstrate for the first time in an experimental model that MMP-2 and MMP-9 cooperate in promoting the in vivo invasive and angiogenic phenotype of malignant keratinocytes. [less ▲]

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See detailSevere inhibition of choroidal neovascularization in mice with a combined deficiency of MMP-2 and MMP-9 genes
Lambert, Vincent ULg; Wielockx, B.; Munaut, Carine ULg et al

in Investigative Ophthalmology & Visual Science (2003, May), 44(Suppl. 2), 410

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See detailMMP-2 and MMP-9 synergize in promoting choroidal neovascularization
Lambert, Vincent ULg; Wielockx, B.; Munaut, Carine ULg et al

in FASEB Journal (2003), 17(15), 2290-2292

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but ... [more ▼]

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization. [less ▲]

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See detailMatrix metalloproteinase-9 contributes to choroidal neovascularization
Lambert, Vincent ULg; Munaut, Carine ULg; Jost, M. et al

in American Journal of Pathology (2002), 161(4), 1247-1253

Age-related macular degeneration (AMD) is the primary cause of irreversible photoreceptors loss in adult patients and current therapies are limited. Increased levels of matrix metalloproteinases (MMPs ... [more ▼]

Age-related macular degeneration (AMD) is the primary cause of irreversible photoreceptors loss in adult patients and current therapies are limited. Increased levels of matrix metalloproteinases (MMPs) have been documented in neovascularization of severe ocular pathologies such as AMD and proliferative diabetic retinopathy. We report here that MMP-9 (gelatinase B) expression is induced and temporally regulated in the course of experimental choroidal neovascularization. We used transgenic mice expressing beta-galactosidase reporter gene under the dependence of MMP-9 promoter and RT-PCR analysis on choroidal neovascular structures microdissected from serial sections by laser pressure catapulting to show that MMP-9 expression is up-regulated concomitantly with the appearance of inflammatory cells in the subretinal lesion. In mice deficient in MMP-9 expression the development of choroidal neovascularization induced by laser photocoagulation still occurred, but at a reduced level. [less ▲]

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