Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells

Bellosta, Stefano; Baetta, Roberta; Canavesi, M.; Comparato, Carmen; Granata, Agnese; Monetti, Mara; Cairoli, F.; Eberini, Ivano; Puglisi, L.; Corsini, Alberto

doi:10.1016/j.phrs.2007.05.004

Cited by 17 publications

(18 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this study, Orm was observed to decrease the transcriptional activation of NF-kB induced by RANKL. Similar effects were observed in Ral-treated groups as reported earlier (Bellosta et al 2007, Lee et al 2008. The attenuation of NF-kB by Orm might lead to suppression of cytokines, e.g.…”

Section: Discussionsupporting

confidence: 89%

Ormeloxifene inhibits osteoclast differentiation in parallel to downregulating RANKL-induced ROS generation and suppressing the activation of ERK and JNK in murine RAW264.7 cells

Kharkwal

Chandra²,

Fatima³

et al. 2012

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Ormeloxifene (Orm), a triphenylethylene compound, has been established as a selective estrogen receptor modulator (SERM) that suppresses the ovariectomy-induced bone resorption in rats. However, the precise mechanism underlying the bone-preserving action of Orm remains unclear. In this study, we evaluated the effect of Orm on osteoclast formation induced by receptor activator of nuclear factor kB ligand (RANKL) in the murine macrophage cell line RAW264.7. We also explored the mechanism of action of Orm by studying the RANKL-induced signaling pathways required for osteoclast differentiation. We found that Orm inhibited osteoclast formation from murine macrophage RAW264.7 cells induced by RANKL in a dose-dependent manner. Orm was able to abolish RANKL-induced reactive oxygen species (ROS) elevation and inhibited the transcriptional activation of two key RANKL-induced transcription factors namely activator protein-1 (AP-1) and NF-kB through mechanisms involving MAPKs. Activation of two MAPKs, i.e. ERK (MAPK1) and JNK (MAPK8), was alleviated by Orm effectively, which subsequently affected the activation of c-Jun and c-Fos, which are the essential components of the AP-1 transcription complex. Taken together, our results demonstrate that Orm potentially inhibits osteoclastogenesis by inhibiting ROS generation and thereby suppressing the activation of ERK1/2 (MAPK3/MAPK1) and JNK (MAPK8) and transcription factors (NF-kB and AP-1), which subsequently affect the regulation of osteoclastogenesis. These results provide a possible mechanism of action of Orm in regulating osteoclastogenesis, thereby supporting the beneficial bone-protective effects of this compound.

show abstract

Section: Discussionsupporting

confidence: 89%

Ormeloxifene inhibits osteoclast differentiation in parallel to downregulating RANKL-induced ROS generation and suppressing the activation of ERK and JNK in murine RAW264.7 cells

Kharkwal

Chandra²,

Fatima³

et al. 2012

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…Immunohistochemical analysis revealed that immunoreactivity of MMP-2 increased in collared arteries in accordance with the results of zymography. Similarly, Bellosta et al 47 reported that carotid lesions of control rabbits showed marked immunoreactivity to MMP-2. Moreover in our study, treatment with TAK-044 decreased the enhanced immunoreactivity of MMP-2.…”

Section: Discussionmentioning

confidence: 81%

MMP-2 and MMP-9 Alteration in Response to Collaring in Rabbits: The Effects of Endothelin Receptor Antagonism

Reel

Oktay

Özkal

et al. 2009

J Cardiovasc Pharmacol Ther

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs), and, in particular, gelatinases (MMP-2 and MMP-9), have been implicated in vascular cell proliferation and/or migration, contributing to intimal thickening, an essential stage in the development of atherosclerosis and restenosis following balloon angioplasty. Endothelin, a strong chemoatractant and mitogen, has been shown to promote smooth muscle cell proliferation and migration by activating MMPs via endothelin-A (ETA) receptors. The positioning of a soft silicon collar around the left carotid artery in rabbits results in intimal thickening. In this study, we investigate the possible role of gelatinases and the effect of a nonselective ETA/ETB receptor antagonist, TAK-044 (5 mg/kg body weight/day, subcutaneously [sc]), on these enzymes. Our results demonstrated that both MMP-2 and MMP-9 activities increased in response to collaring in placebo group, while treatment with TAK-044 significantly suppressed both gelatinase activities and proMMP-2 levels, and inhibited intimal thickening in collared arteries. These results suggest that either enhanced MMP expression or endothelin receptor antagonism may be involved in the formation of intimal thickening in this model.

show abstract

“…NF-κB is known to regulate inflammatory responses by overexpression of chemokines and leukocyte adhesion molecules and subsequently recruit monocyte-derived macrophages into the arterial wall to from of lipid-rich foam cells [3, 8, 9]. In addition, NF-κB action has been shown to upregulate the proliferation of vascular smooth muscle cells (VCMS) and expressions of MMPs in VCMS [58–60]. Nuclear localization of p65 has been detected in ECs, VCMS and macrophage [58–60].…”

Section: Discussionmentioning

confidence: 99%

Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway

Jia

Nallasamy

Liu

et al. 2015

The Journal of Nutritional Biochemistry

160

101

View full text Add to dashboard Cite

Vascular inflammation plays a significant role in the pathogenesis of atherosclerosis. Luteolin, a naturally-occurring flavanoid, present in many medicinal plants as well as in some commonly consumed fruits and vegetables has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of luteolin at physiological concentrations remain unclear. Here, we report that luteolin as low as 0.5 μM significantly inhibited TNF-α-induced adhesion of monocytes to human EA.hy 926 endothelial cells, a key event in triggering vascular inflammation. Luteolin potently suppressed TNF-α-induced expression of the chemokine monocyte chemotactic protein-1 (MCP-1) and adhesion molecules ICAM-1 and VCAM-1, key mediators involved in enhancing endothelial cell-monocyte interaction. Furthermore, luteolin inhibited TNF-α-induced NF-κB transcriptional activity, IκBα degradation, expression of IκB kinase ß (IKKß), and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that luteolin can inhibit inflammation by suppressing NF-κB signaling. In an animal study, C57BL/6 mice were fed a diet containing 0% or 0.6% luteolin for three weeks and luteolin supplementation greatly suppressed TNF-α-induced increases in circulating levels of MCP-1/JE, CXCL1/KC, and sICAM-1 in C57BL/6 mice. Consistently, dietary intake of luteolin significantly reduced TNF-α-stimulated adhesion of monocytes to aortic endothelial cells ex vivo. Histology shows that luteolin treatment prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers’ delicate organization as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies further show that luteolin treatment also reduced VCAM-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, luteolin protects against TNF-α-induced vascular inflammation, in both in vitro and in vivo models. This anti-inflammatory effect of luteolin may be mediated via inhibition of the NF-κB-mediated pathway.

show abstract

Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells

Cited by 17 publications

References 47 publications

Ormeloxifene inhibits osteoclast differentiation in parallel to downregulating RANKL-induced ROS generation and suppressing the activation of ERK and JNK in murine RAW264.7 cells

Ormeloxifene inhibits osteoclast differentiation in parallel to downregulating RANKL-induced ROS generation and suppressing the activation of ERK and JNK in murine RAW264.7 cells

MMP-2 and MMP-9 Alteration in Response to Collaring in Rabbits: The Effects of Endothelin Receptor Antagonism

Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway

Contact Info

Product

Resources

About