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

Geetika Kharkwal, Vishal Chandra, Iram Fatima, Anila Dwivedi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 κB 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-κB 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-κB 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.

Original languageEnglish (US)
Pages (from-to)261-270
Number of pages10
JournalJournal of Molecular Endocrinology
Volume48
Issue number3
DOIs
StatePublished - Jun 1 2012

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Osteoclasts
Down-Regulation
Transcription Factor AP-1
Osteogenesis
Reactive Oxygen Species
Transcription Factors
Macrophages
Selective Estrogen Receptor Modulators
ormeloxifene
Bone and Bones
Ovariectomy
Bone Resorption
Cytoplasmic and Nuclear Receptors
Transcriptional Activation
Ligands
Cell Line

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

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, Geetika; Chandra, Vishal; Fatima, Iram; Dwivedi, Anila.

In: Journal of Molecular Endocrinology, Vol. 48, No. 3, 01.06.2012, p. 261-270.

Research output: Contribution to journalArticle

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