In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague–Dawley rats by ormeloxifene, a selective estrogen receptor modulator

Arshad, Mohammad; Sengupta, Surojeet; Sharma, Shivani; Ghosh, Rumi; Sawlani, Vijay; Singh, Man Mohan

doi:10.1016/j.jsbmb.2004.02.010

Cited by 26 publications

(22 citation statements)

References 28 publications

(36 reference statements)

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“…New synthetic, non-steroidal compounds, called the selective estrogen receptor (ER) modulators or SERMs, have recently been shown to possess ER agonistic or antagonistic selectivity depending on the target tissue [5]. Ormeloxifene is a member of type-1 class of non-steroidal SERMs in clinical use [6], which possesses desirable bone-protective [7][8][9][10] and lipid lowing activities [11] of estrogen and reported to prevent advanced breast cancer in both women and men [6,12,13] without side effects associated with conventional HRT/ERT. The precise mechanism by which ormeloxifene and other such SERMs exert tissue-specific estrogen agonist/antagonistic effect remains enigmatic.…”

Section: Introductionmentioning

confidence: 99%

Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression

Murthy

Sengupta

Sharma

et al. 2006

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Introductionmentioning

confidence: 99%

Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression

Murthy

Sengupta

Sharma

et al. 2006

The Journal of Steroid Biochemistry and Molecular Biology

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“…01, *P!0 . 05 vs VCRL; loss in rats (Arshad et al 2004, Narayana Murthy et al 2006. This study was carried out to investigate the influence of Orm on the generation of osteoclast and its mechanism of action using an in vitro model system, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Orm has also shown anticancer activity in phase II and III clinical trials conducted on terminal cases of breast cancer (Misra et al 1989). Besides antibreast cancer activity, Orm has been demonstrated to cause the inhibition of estrogen-deficient osteoporosis in rats (Arshad et al 2004). It induced the apoptosis of osteoclasts via upregulation of TGFb3 (TGFB3) expression in rat (Narayana Murthy et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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

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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.

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“…Our studies have revealed that in Orm treated group, uterine ER could not induce the formation of AP-1 complexes. Previous studies have demonstrated that Orm exhibits antiestrogenic activity in uterus [16,23] as well as in MCF-7 breast cancer cells [24] whereas in bone it is estrogenic [25,26]. It binds to both ER isoforms [17].…”

Section: Discussionmentioning

confidence: 99%

Modulation of AP-1 mediated estrogenic response by ormeloxifene in rat uterus

Awasthi

Daverey

Dwivedi

2007

The Journal of Steroid Biochemistry and Molecular Biology

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In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague–Dawley rats by ormeloxifene, a selective estrogen receptor modulator

Cited by 26 publications

References 28 publications

Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression

Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression

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

Modulation of AP-1 mediated estrogenic response by ormeloxifene in rat uterus

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