Activation of peroxisome proliferator-activated receptor γ inhibits TNF-α-mediated osteoclast differentiation in human peripheral monocytes in part via suppression of monocyte chemoattract
- 作者：Hiroyuki Hounoki ; Eiji Sugiyama ; Saad Gad-Kamel Mohamed ; Kouichiro Shinoda ; Hirofumi Taki ; Hekmat Osman Abdel-Aziz ; Muneharu Maruyama ; Masashi Kobayashi ; Tatsuro Miyahara
- 关键词：Osteoclastogenesis ; TNF-
//www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0"> ; PPARγ ; MCP-1 ; Human monocytes
- 刊名：Bone
- 出版年：2008
- 期刊代码：39_87563282
- 类别：med
- 出版时间：April 2008
- 卷：42
- 期：4
- 页码：765-774
- 文件大小：1586 K
摘要
Tumor necrosis factor-
alpha" title="greek small letter alpha" border="0"> (TNF-alpha" title="greek small letter alpha" border="0">) plays critical roles in bone resorption at the site of inflammatory joints. The aim of this study is to evaluate the effect of peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, a new class of anti-inflammatory compounds, on TNF-alpha" title="greek small letter alpha" border="0">-mediated osteoclastogenesis in human monocytes. Human monocytes were differentiated into osteoclasts in the presence of TNF-alpha" title="greek small letter alpha" border="0"> and macrophage colony-stimulating factor. Tartrate-resistant acid phosphatase (TRAP) staining and a pit formation assay using dentin were used for the identification of activated osteoclasts. The protein and gene expressions of transcription factors were determined by immunofluorescence and real-time RT-PCR analysis, respectively. TNF-alpha" title="greek small letter alpha" border="0">-induced osteoclast generation from human peripheral monocytes in a dose-dependent manner, and the induction was not inhibited by osteoprotegerin, a decoy receptor for receptor activator of NF-κB ligand. The addition of PPAR-γ agonists, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, to the culture resulted in a remarkably reduced number of generated osteoclasts. In addition, both agonists inhibited the protein and gene expressions of nuclear factor of activated T-cell isoform c1 (NFATc1), c-Fos, c-Jun and NF-κB p65, which are known to be associated with osteoclastogenesis. GW9662, an antagonist of PPAR-γ, fully rescued ciglitazone-induced inhibition, but did not affect 15d-PGJ2-induced inhibition. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine related to osteoclastogenesis, was induced during TNF-alpha" title="greek small letter alpha" border="0">-mediated osteoclast differentiation, and the neutralizing antibody to MCP-1 reduced osteoclast formation by about 40%. 15d-PGJ2 and ciglitazone blocked the induction of MCP-1 by TNF-alpha" title="greek small letter alpha" border="0">. Moreover, the addition of MCP-1 rescued the inhibition of TRAP-positive multinucleated cell (TRAP-MNCs) formation by 15d-PGJ2 and ciglitazone, although generated TRAP-MNCs had no capacity to resorb dentin slices. Our data demonstrate that 15d-PGJ2 and ciglitazone down-regulate TNF-alpha" title="greek small letter alpha" border="0">-mediated osteoclast differentiation in human cells, in part via suppression of the action of MCP-1. These PPAR-γ agonists may be a promising therapeutic application for rheumatoid arthritis and inflammatory bone-resorbing diseases.
alpha" title="greek small letter alpha" border="0"> (TNF-alpha" title="greek small letter alpha" border="0">) plays critical roles in bone resorption at the site of inflammatory joints. The aim of this study is to evaluate the effect of peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, a new class of anti-inflammatory compounds, on TNF-alpha" title="greek small letter alpha" border="0">-mediated osteoclastogenesis in human monocytes. Human monocytes were differentiated into osteoclasts in the presence of TNF-alpha" title="greek small letter alpha" border="0"> and macrophage colony-stimulating factor. Tartrate-resistant acid phosphatase (TRAP) staining and a pit formation assay using dentin were used for the identification of activated osteoclasts. The protein and gene expressions of transcription factors were determined by immunofluorescence and real-time RT-PCR analysis, respectively. TNF-alpha" title="greek small letter alpha" border="0">-induced osteoclast generation from human peripheral monocytes in a dose-dependent manner, and the induction was not inhibited by osteoprotegerin, a decoy receptor for receptor activator of NF-κB ligand. The addition of PPAR-γ agonists, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, to the culture resulted in a remarkably reduced number of generated osteoclasts. In addition, both agonists inhibited the protein and gene expressions of nuclear factor of activated T-cell isoform c1 (NFATc1), c-Fos, c-Jun and NF-κB p65, which are known to be associated with osteoclastogenesis. GW9662, an antagonist of PPAR-γ, fully rescued ciglitazone-induced inhibition, but did not affect 15d-PGJ2-induced inhibition. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine related to osteoclastogenesis, was induced during TNF-alpha" title="greek small letter alpha" border="0">-mediated osteoclast differentiation, and the neutralizing antibody to MCP-1 reduced osteoclast formation by about 40%. 15d-PGJ2 and ciglitazone blocked the induction of MCP-1 by TNF-alpha" title="greek small letter alpha" border="0">. Moreover, the addition of MCP-1 rescued the inhibition of TRAP-positive multinucleated cell (TRAP-MNCs) formation by 15d-PGJ2 and ciglitazone, although generated TRAP-MNCs had no capacity to resorb dentin slices. Our data demonstrate that 15d-PGJ2 and ciglitazone down-regulate TNF-alpha" title="greek small letter alpha" border="0">-mediated osteoclast differentiation in human cells, in part via suppression of the action of MCP-1. These PPAR-γ agonists may be a promising therapeutic application for rheumatoid arthritis and inflammatory bone-resorbing diseases.