Activation of peroxisome proliferator-activated receptor γ inhibits TNF-α-mediated osteoclast differentiation in human peripheral monocytes in part via suppression of monocyte chemoattractant protein-1 expression

• Published in: Bone (New York, N.Y.) N.Y.), 2008-04, Vol.42 (4), p.765-774
• Main Authors: Hounoki, Hiroyuki, Sugiyama, Eiji, Mohamed, Saad Gad-Kamel, Shinoda, Kouichiro, Taki, Hirofumi, Abdel-Aziz, Hekmat Osman, Maruyama, Muneharu, Kobayashi, Masashi, Miyahara, Tatsuro
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Differentiation - drug effects; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cells, Cultured; Chemokine CCL2 - metabolism; Fundamental and applied biological sciences. Psychology; Human monocytes; Humans; MCP-1; Molecular and cellular biology; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Orthopedics; Osteoclastogenesis; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - metabolism; PPAR gamma - metabolism; PPARγ; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; RANK Ligand - metabolism; Thiazolidinediones - pharmacology; TNF-α; Transcription Factors - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2007.11.016

Abstract Tumor necrosis factor-α (TNF-α) 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-α-mediated osteoclastogenesis in human monocytes. Human monocytes were differentiated into osteoclasts in the presence of TNF-α 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-α-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-α-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-α. 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-α-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.