A selective estrogen receptor modulator inhibits tumor necrosis factor-α-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes.

Abstract

Tumor necrosis factor α (TNF-α) is a pleiotropic cytokine mediating inflammatory as well as cell death activities, and is thought to induce chondrocytic chondrolysis in inflammatory and degenerative joint diseases. Selective estrogen receptor modulators (SERMs), such as raloxifene, which are commonly used in clinical settings act as estrogen agonists or antagonists. It is assumed that estrogens have a potential role in cartilage protection; however, the precise molecular mechanism for the protective effects of estrogens is unclear. This study was designed to examine whether raloxifene inhibits TNF-α-induced apoptosis in human chondrocytes and to clarify the mechanisms involved. We also investigated the signaling pathways responsible for the anti-apoptotic effect of raloxifene. Apoptosis in chondrocytes was determined by DNA fragmentation assay and caspase-3 activation. Raloxifene significantly inhibited TNF-α-induced caspase-3 activation and cell DNA fragmentation levels in chondrocytes. The inhibitory effect of raloxifene was abolished by the estrogen receptor antagonist ICI 182,780. Extracellular signal-regulated kinase 1/2 (ERK1/2) regulates apoptosis, acting as an apoptotic or anti-apoptotic signal. TNF-α-induced apoptosis was significantly enhanced by the ERK1/2 pathway inhibitor PD98059. Raloxifene stimulated a further increase in ERK1/2 phosphorylation in TNF-α-treated chondrocytes. Furthermore, the anti-apoptotic effects of raloxifene were inhibited by PD98059. In addition, the anti-apoptotic effects of raloxifene were completely abolished in ERK1/2 siRNA-treated chondrocytes. These results suggest that raloxifene prevents caspase-3-dependent apoptosis induced by TNF-α in human chondrocytes by activating estrogen receptors and the ERK1/2 signaling pathway.

• Authors: Yosuke Hattori, Toshihisa Kojima, Daizo Kato, Hiroyuki Matsubara, Masaharu Takigawa, Naoki Ishiguro
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 421 Issue 3 Pg. 418-24 (May 11 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 22480687 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• RNA, Small Interfering
• Selective Estrogen Receptor Modulators
• Tumor Necrosis Factor-alpha
• Raloxifene Hydrochloride
• Proto-Oncogene Proteins c-akt
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival
• Chondrocytes (drug effects, enzymology)
• Enzyme Activation
• Humans
• MAP Kinase Kinase 4 (biosynthesis)
• MAP Kinase Signaling System
• Mitogen-Activated Protein Kinase 1 (biosynthesis, genetics)
• Mitogen-Activated Protein Kinase 3 (biosynthesis, genetics)
• Proto-Oncogene Proteins c-akt (biosynthesis)
• RNA, Small Interfering (genetics)
• Raloxifene Hydrochloride (pharmacology)
• Selective Estrogen Receptor Modulators (pharmacology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, pharmacology)
• p38 Mitogen-Activated Protein Kinases (biosynthesis)