Stromelysin-1 (MMP-3) expression driven by a macrophage-specific promoter results in reduced viability in transgenic mice

Myeloid lineage cells contribute to innate and acquired immunity, homeostasis, wound repair, and inflammation. There is considerable interest in manipulation of their function in transgenic mice using myeloid-specific promoters. This review considers the applications and specificity of some of the most widely studied transgenes, driven by promoter elements of the lysM, csf1r, CD11c, CD68, macrophage SRA, and CD11b genes, as well as several others. Transgenes have been used in mice to generate myeloid lineage-specific cell ablation, expression of genes of interest, including fluorescent reporters, or deletion via recombination. In general, the specificity of such transgenes has been overinterpreted, and none of them provide well-documented, reliable, differential expression in any specific myeloid cell subset, macrophages, granulocytes, or myeloid DCs. Nevertheless, they have proved valuable in cell isolation, functional genomics, and live imaging of myeloid cell behavior in many different pathologies.

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“…Expression in macrophages [143], but evidence of specificity using a luciferase reporter was not compelling [144]. CD11b…”

Section: Visna Virus Ltrmentioning

confidence: 99%

Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity

Hume

2010

Journal of Leukocyte Biology

130

144

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“…• Caused prenatal or neonatal death in mice constitutively expressing MMP-3 in tissue macrophages • Developed premalignant and malignant lesions in the mammary glands of transgenic mice expressing an autoactivating form of MMP-3 [35,36] MMP-9…”

Section: Mmp-3mentioning

confidence: 99%

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Skiles¹,

Gonnella²,

Jeng³

2001

CMC

211

144

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Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

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“…Plaque rupture occurs in various pathological states and is typically associated with matrix metalloproteinases (MMPs). MMPs are able to degrade collagen and other extracellular matrix (ECM) components that compose the major structure of plaques and previous studies have indicated an association between the level of MMPs and plaque stability (5–7). Co-expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and MMPs has been observed in macrophages in vitro and in human atheroma, particularly in the shoulder region of VP atheroma (8).…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin attenuates plaque vulnerability by downregulation of EMMPRIN expression via COX-2/PGE2 pathway

Lü

Yang

Guo

et al. 2017

Experimental and Therapeutic Medicine

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Extracellular matrix metalloproteinase inducer (EMMPRIN) reportedly has a key regulatory role in matrix metalloproteinase (MMP) activities and the progression of atherosclerosis. Statins, which are anti-atherosclerotic pharmacological agents, are widely applied in clinical settings. The aim of the present study was to investigate the pharmaceutical effect of atorvastatin on EMMPRIN expression in atherosclerotic plaques. An atherosclerotic mouse model was established using apoliprotein E-deficient (ApoE−/−) mice raised on a high-fat diet. Additionally, a low (5 mg/kg/day) or high dosage (10 mg/kg/day) of atorvastatin suspension was administered orally for eight weeks, beginning on week 7 or 11 respectively. The effects of atorvastatin on atherosclerotic plaque formation and EMMPRIN expression were subsequently determined. The THP-1 cell line was used to investigate the effect of atorvastatin on EMMPRIN expression in vitro. The results demonstrated that the high-fat diet led to vulnerable plaques (VPs) and increased EMMPRIN expression in VPs in ApoE−/− mice. Atorvastatin treatment decreased EMMPRIN expression in the aortas and plaques of ApoE−/− mice. In vitro, oxidized low-density lipoprotein (ox-LDL) induced the expression of cyclooxygenase-2 (COX-2) and EMMPRIN in THP-1 macrophages, and atorvastatin inhibited ox-LDL-induced expression of PGE2, EMMPRIN and COX-2 in THP-1 macrophages. Therefore, the present data indicated that atorvastatin treatment reduces the vulnerability of atherosclerotic plaques and expression of EMMPRIN, and that the inhibitory effect of atorvastatin on EMMPRIN may occur via the COX-2/PGE2 signaling pathway in macrophages.

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Stromelysin-1 (MMP-3) expression driven by a macrophage-specific promoter results in reduced viability in transgenic mice

Cited by 3 publications

References 27 publications

Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity

Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Atorvastatin attenuates plaque vulnerability by downregulation of EMMPRIN expression via COX-2/PGE2 pathway

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