Stimulatory Effect of Endogenous Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Overexpression on Type IV Collagen and Laminin Gene Expression in Rat Mammary Carcinoma Cells

Yoshiji, Hitoshi; Buck, Todd; Harris, Steven R.; Ritter, Linda M.; Lindsay, Carol K.; Thorgeirsson, Unnur P.

doi:10.1006/bbrc.1998.8805

Cited by 14 publications

(10 citation statements)

References 18 publications

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“…It may be that TIMP-3 is involved in an intracellular signalling pathway that actually inhibits MMP-9 expression. In an earlier study, TIMP-1 stimulated the gene expression of type IV collagen and laminin [29]. It is also plausible that TIMP-3 is actually inhibiting the activation of latent MMP-9.…”

Section: Discussionmentioning

confidence: 90%

Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-3 Are Key Regulators of Extracellular Matrix Degradation by Mouse Embryos1

Whiteside

Jackson

Herington

et al. 2001

Biology of Reproduction

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Embryo implantation in humans and rodents is a highly invasive yet tightly controlled process involving extracellular matrix (ECM) degradation. Matrix metalloproteinase 9 (MMP-9) has been implicated as the major facilitator of this ECM degradation. MMP-9 is expressed by the embryo's trophoblast cells, whereas tissue inhibitor of metalloproteinases 3 (TIMP-3) is expressed by the maternal uterine cells immediately adjacent to the trophoblast. We examined the functional roles of MMP-9 and TIMP-3 during in vitro ECM degradation by mouse embryos. Blastocysts were treated with either MMP-9 antisense or sense oligonucleotides and incubated on an ECM gel. The extent of ECM degradation exhibited by the blastocysts due to proteinase secretion was quantified. Embryos exposed to MMP-9 antisense oligonucleotides exhibited reduced ECM-degrading activity as compared with controls, and this reduced activity was correlated with the level of MMP-9 secreted by the embryos. The functional role of TIMP-3 was then examined by incubating blastocysts on an ECM gel that had been impregnated with various amounts of TIMP-3. In a dose-dependent manner, increases in TIMP-3 resulted in a reduction in ECM degradation and were correlated with diminished MMP-9 activity. These results provide important functional evidence that in vitro ECM degradation is regulated by embryo-derived MMP-9 and ECM-derived TIMP-3.

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Section: Discussionmentioning

confidence: 90%

Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-3 Are Key Regulators of Extracellular Matrix Degradation by Mouse Embryos1

Whiteside

Jackson

Herington

et al. 2001

Biology of Reproduction

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“…Although the canonical role that has been assigned to TIMPs is that of inhibiting the active forms of MMPs, a growing body of evidence suggests that TIMPs exert effects that cannot be ascribed to their ability to attenuate active MMPs. Indeed, TIMPs have been shown to both stimulate and inhibit cell growth, prevent angiogenesis, as well as regulate cell survival and cell apoptosis (2,11,18,24,38,39). Although TIMP-1 and -3 and TIMP-2 and -4 share sequence homologies, the reasons for the significant functional differences among TIMP-1, -2, -3, and -4 are not known, underscoring the need for mapping the regions of TIMPs that are responsible for these activities to better understand the novel structure-function relationships of these molecules.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts

Lovelock¹,

Baker²,

Gao³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

119

123

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The balance between matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), plays a critical role in cardiac remodeling. Although a number of studies have characterized the pathophysiological role of MMPs in the heart, very little is known with respect to the role of TIMPs in the heart. To delineate the role of TIMPs in the heart we examined the effects of adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 in cardiac fibroblasts. Infection of cardiac fibroblasts with adenoviral constructs containing human recombinant TIMP (AdTIMP-1, -2, -3, and -4) provoked a significant (P < 0.0001) 1.3-fold in increase in bromodeoxyuridine (BrdU) incorporation. Similarly, treatment of cardiac fibroblasts with AdTIMP-1-, -2-, -3-, and -4-conditioned medium led to a 1.2-fold increase in BrdU incorporation (P < 0.0001) that was abolished by pretreatment with anti-TIMP-1, -2, -3, and -4 antibodies. The effects of TIMPs were not mimicked by treating the cells with RS-130830, a broad-based MMP inhibitor, suggesting that the effects of TIMPs were independent of their ability to inhibit MMPs. Infection with AdTIMP-1, -2, -3, and -4 led to a significant increase in alpha-smooth muscle actin staining, consistent with TIMP-induced phenotypic differentiation into myofibroblasts. Finally, infection with AdTIMP-2 resulted in a significant increase in collagen synthesis, whereas infection with AdTIMP-3 resulted in a significant increase in fibroblast apoptosis. TIMPs exert overlapping as well as diverse effects on isolated cardiac fibroblasts. The observation that TIMPs stimulate fibroblast proliferation as well as phenotypic differentiation into myofibroblasts suggests that TIMPs may play an important role in tissue repair in the heart that extends beyond their traditional role as MMP inhibitors.

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“…Because the overall expression of TIMPs, MMPs, and/or the MMP/TIMP ratio are probably crucial to achieve a balance and maintain bone mass constant, we also investigated the effect of TIMP‐1 overexpression on TIMP‐2 and MMP‐13 expression in male and female TG mice. There are several controversial reports indicating that overexpression of TIMP‐1 in different types of cells affects or does not affect other TIMP or MMP expression levels in vitro ( 38,39 ) or in vivo. ( 40–43 ) We showed here that neither TIMP‐2 nor MMP‐13 expression was affected.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Inhibition of Osteoblastic Metalloproteinases Leads to Increased Trabecular Bone Mass

Geoffroy

Marty-Morieux

Goupil

et al. 2004

Journal of Bone and Mineral Research

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Mice specifically overexpressing TIMP-1 in osteoblasts have been generated to investigate the role of MMPs in bone in vivo. These mice displayed increased trabecular bone volume and decreased bone turnover. This model provides evidence of the role played by the MMPs in bone remodeling and balance.Introduction: Although it has been suggested that the matrix metalloproteinases (MMPs) may play a role in initiating the bone resorption process in vitro, there is no evidence that they play any role in in vivo bone maintenance. Materials and Methods:We used an artificial promoter specifically driving cells of the osteoblastic lineage to overexpress the tissue inhibitor of MMPs (TIMP-1) cDNA in mice. Densitometric analysis, using DXA and pQCT, and static and dynamic histomorphometry were used to evaluate the bone phenotype both in male and female transgenic mice. We evaluated osteoblastic differentiation using a primary osteoblast culture and osteoclast activity using an ex vivo organ culture. Results and Conclusion:We showed that at 1 and 2.5 months of age, only the female mice exhibited a bone phenotype. These mice displayed specific increases in the BMD and bone volume of trabecular bone. This increase was accompanied by decreased trabecular separation, suggesting a decrease in bone resorption. Using an ex vivo resorption assay, we demonstrated that parathyroid hormone (PTH)-stimulated bone resorption was reduced in these mice. Evaluation of the bone histomorphometric dynamic parameters showed that the mineralizing surfaces and bone formation rate were both reduced. There was no change in the mineralization lag time or number of osteocyte lacunae. Using primary osteoblast culture and molecular analysis, we showed that the differentiation and function of osteoblasts from transgenic mice were normal, but that the ex vivo formation of mineralized nodules was delayed. This model is the first to show that in vivo MMPs play a role in bone remodeling and bone balance. Moreover, our data suggest that MMP activity could be involved in the hormonal regulation of bone resorption by osteoblasts.

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Stimulatory Effect of Endogenous Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Overexpression on Type IV Collagen and Laminin Gene Expression in Rat Mammary Carcinoma Cells

Cited by 14 publications

References 18 publications

Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-3 Are Key Regulators of Extracellular Matrix Degradation by Mouse Embryos1

Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-3 Are Key Regulators of Extracellular Matrix Degradation by Mouse Embryos1

Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts

In Vivo Inhibition of Osteoblastic Metalloproteinases Leads to Increased Trabecular Bone Mass

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