The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.ectoplacental cone | fetus P reeclampsia (PE) is one of the most common pregnancy complications worldwide, affecting ∼3% to 8% of all pregnancies, and is a leading cause of perinatal and maternal morbidity and mortality (1). PE is characterized by placental hypoperfusion and shallow trophoblast invasion of uterine blood vessels (2) that is particularly evident in the severe cases that commence early in pregnancy (3). Adequate trophoblast invasion is vital to provide the embryo with access to oxygen and nutrients, and, in human and mouse, the placenta is thereby in direct contact with maternal blood. The clinical diagnostic criteria of this syndrome include widespread maternal endothelial dysfunction as evidenced by hypertension, proteinuria, and peripheral and/or cerebral edema (4). In addition to the maternal signs, PE is also frequently associated with intrauterine growth restriction (IUGR) and prematurity (5). The etiology of PE is unclear and the only known cure is delivery of the placenta. The upstream regulatory mechanisms remain elusive, as do the downstream consequences that lead to the maternal signs. Nevertheless, there is substantial evidence for contributing factors including abnormal placentation, particularly the invasive component. Restricted invasion is thought to be a reflection of defects in the cytotrophoblast (CTB) differentiation pathway that is required for uterine interstitial and endovascular invasion. Specifically, CTBs, which are epithelial cells of ectodermal origin, acquire vascularlike properties, and this transformation is dysregulated in PE (3, 6). The rudimentary endovascular invasion is thought to lead to the release of pathologic factors such as va...

TH. Rinkenberger JL & Coussens LM. Matrix-degrading proteases and angiogenesis during development and tumor formation. APMIS 1999; 107: 1 1-8.Embryonic development and tumor progression both require the exquisite coordination of programs for extracellular matrix (ECM) formation and remodeling, and those for angiogenesis and vascular development. Without a vascular supply the normal tissue or tumor is limited in size and organization. Without ECM remodeling the alteration of tissue and tumor boundaries and cellular migrations are limited. Recent insights into the molecular mechanisms regulating the extracellular environment of the growing embryonic tissue or tumors have implicated proteases, the matrix metalloproteinases (MMPs) in particular, in both the process of ECM remodeling and angiogenesis, and in a potential causal relationship between these processes. This review focuses on the roles that. MMPs play in regulating three processes in which both proteolysis and vascular development are tightly coordinated: embryo implantation, bone development and tumor progression.Embryonic implantation, endochondral bone formation and tumor growth are processes requiring both modification of the ECM microenvironment and recruitment of new blood vessels ( I , 2). In this review we discuss how genetic modifications in mice have made it possible to show that ECM remodeling by proteases and their inhibitors is intimately related to the angiogenic program.

Cytokine regulation of B cell development was analyzed using interleukin-2 (IL-2)-induced transcription of the J chain gene as a model system. A nuclear target of the IL-2 signal was identified as the Pax5 transcription factor, BSAP, which recognizes a negative regulatory motif in the J chain promoter. Functional assays showed that BSAP mediates the silencing of the J chain gene during the early stages of B cell development, but repression is relieved during the antigen-driven stages in a concentration-dependent manner by an IL-2-induced down-regulation of BSAP RNA expression. At the low levels present in J chain-expressing plasma cells, BSAP repression could be overridden by positive-acting factors binding to down-stream J chain promoter elements. Overexpression of BSAP in these cells reversed the positive regulation and inhibited J chain gene transcription. Thus, IL-2 regulation of BSAP concentration may provide a mechanism for controlling both repressor and activator functions of BSAP during a B cell immune response.

αvβ6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits αvβ6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey αvβ6, and inhibits binding to all ligands including the latency-associated peptide of TGF-β. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin αvβ8, but not the integrins α5β1, αvβ3, αvβ5 and α4β1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and αvβ6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-β-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-β by NCI-H358 tumour cells in a tumour cell-fibroblast co-culture assay. In vivo 264RAD showed dose-dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of αvβ6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of αvβ6 integrin, with some activity against αvβ8 integrin, that reduces both tumour growth and metastasis.

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