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

Murthy, P. S. Narayana; Sengupta, Surojeet; Sharma, Shikha; Singh, Man Mohan

doi:10.1016/j.jsbmb.2006.03.009

Cited by 24 publications

(17 citation statements)

References 30 publications

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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%

“…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). However, the precise mechanism by which Orm exerts its tissue-specific estrogen agonistic effect and also the antiosteoclastogenic effect remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Estradiol was initially suggested to inhibit osteoclasts by increasing the production of TGFβ (Yang et al 1996;Robinson et al 1996). 17β-Estradiol can release TGFβ from osteoblasts but can also release it by direct action on osteoclasts (Robinson et al 1996;Yang et al 1996;Narayana Murthy et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Comparison of morphological effects of PGE2 and TGFβ on osteoclastogenesis induced by RANKL in mouse bone marrow cell cultures

Gardner¹

2007

Cell Tissue Res

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RANKL, in the presence of M-CSF, induces the development and fusion of TRAP+ osteoclasts in mouse bone marrow cultures at 3-5 days. Early during culture (day 3), most cells are small (up to six nuclei). At lower cell densities, these osteoclasts exhibit a rounded morphology with cytoplasm extending around the cells but, at higher densities, this changes to a stellate morphology with the cytoplasm being retracted around the nuclei with numerous localised cytoplasmic extensions. Under optimal conditions, osteoclast fusion results in conglomerates of many cells, which become large cytoplasmic masses on day 4. PGE2 and TGFbeta have both been shown to increase osteoclast development in this model and their effects on the morphology of osteoclasts during fusion and differentiation have been compared under all these conditions. PGE2 or TGFbeta increase osteoclast numbers and size and also the number of nuclei, indicating increased osteoclast development and fusion. TGFbeta increases the size of rounded osteoclasts (with respect to the number of nuclei) more than PGE2, suggesting that TGFbeta increases cytoplasmic extension. TGFbeta increases the size and number of nuclei in stellate cells but particularly increases the number and length of the cytoplasmic extensions, in contrast to PGE2. Fusion of these extensions with other osteoclasts results in large networks of interconnected cells. On day 4, spreading cells develop but these are still interconnected by cytoplasmic links, a phenomenon not seen in control wells or after treatment with PGE2. TGFbeta is more effective than PGE2 in increasing fusion in the formation of cell conglomerates and cytoplasmic masses. PGE2 decreases overall cell density resulting in additional indirect effects on osteoclast numbers and morphology. However, PGE2 particularly promotes the formation of large mature spreading osteoclasts later during culture.

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“…44 Due to its different mechanisms of interaction with different estrogen receptors, it selects the tissues it acts upon. Thus, depending on the target organ, it produces antagonistic effects (as in breast and uterus) and does not stimulate estrogenic processes; 45 or agonist effects, in which case it exerts its antiresorptive function.…”

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confidence: 99%

Influence of menopause on endodontic treatment

Gomes‐Filho¹,

Martins²,

Sivieri-Araújo³

et al. 2014

Dental Press Endod

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Menopause is one of the physiological changes characterized by the end of menstrual and ovulatory cycles occuring in women in their fourth and fifth decade of life. Thereat, production of estrogen, an important hormone that acts in many physiological process of the individual such as the regulation of skeletal system, decreases. The decline in estrogen levels results in loss of bone mineral density, increased fracture risk, as well as bone diseases such as osteoporosis, a pathological process in which there is increased resorption of cavities that are not completely filled by newly formed bone. Furthermore, estrogen deficiency can cause many changes in an individual's oral health. In the presence of bacterial infection of pulp tissue, this deficiency can aggravate apical periodontitis. Several drugs have been studied as potential therapeutic agents to compensate for deficiency of estrogen. These drugs aim to reduce the likelihood of fractures and prevent bone loss as well as cardiovascular and mental disorders resulting from postmenopausal hormone disabilities. Raloxifene (RLX) is one of the most studied drugs therapies and proves to prevent bone loss. Even though raloxifene is indicated for and produces benefits to bone metabolism and maintenance of bone density, additional studies are warranted to further investigate the role of raloxifene in endodontic infection of osteopenic organisms.

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

Cited by 24 publications

References 30 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

Comparison of morphological effects of PGE2 and TGFβ on osteoclastogenesis induced by RANKL in mouse bone marrow cell cultures

Influence of menopause on endodontic treatment

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