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ID 49555
フルテキストURL
著者
Takano, Mariko Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Otsuka, Fumio Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Matsumoto, Yoshinori Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Inagaki, Kenichi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Takeda, Masaya Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Nakamura, Eri Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Tsukamoto, Naoko Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Miyoshi, Tomoko Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Sada, Ken-ei Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
Makino, Hirofumi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci
抄録
Recent studies have suggested possible adverse effects of thiazolidinediones on bone metabolism. However, the detailed mechanism by which the activity of PPAR affects bone formation has not been elucidated. Impaired osteoblastic function due to cytokines is critical for the progression of inflammatory bone diseases. In the present study, we investigated the cellular mechanism by which PPAR actions interact with osteoblast differentiation regulated by BMP and TNF-alpha using mouse myoblastic C2C12 cells. BMP-2 and -4 potently induced the expression of various bone differentiation markers including Runx2, osteocalcin, type-1 collagen and alkaline phosphatase (ALP) in C2C12 cells. When administered in combination with a PPAR alpha agonist (fenofibric acid) but not with a PPAR gamma agonist (pioglitazone), BMP-4 enhanced osteoblast differentiation through the activity of PPAR alpha. The osteoblastic changes induced by BMP-4 were readily suppressed by treatment with TNF-alpha. Interestingly, the activities of PPAR alpha and PPAR gamma agonists reversed the suppression by TNF-alpha of osteoblast differentiation induced by BMP-4. Furthermore, TNF-alpha-induced phosphorylation of MAPKs, NF kappa B, I kappa B and Stat pathways was inhibited in the presence of PPAR alpha and PPAR gamma agonists with reducing TNF-alpha receptor expression. In view of the finding that inhibition of SAPK/JNK. Stat and NF kappa B pathways reversed the TNF-alpha suppression of osteoblast differentiation, we conclude that these cascades are functionally involved in the actions of PPARs that antagonize TNF-alpha-induced suppression of osteoblast differentiation. It was further discovered that the PPAR alpha agonist enhanced BMP-4-induced Smad1/5/8 signaling through downregulation of inhibitory Smad6/7 expression, whereas the PPAR gamma agonist impaired this activity by suppressing BMPRII expression. On the other hand, BMPs increased the expression levels of PPAR alpha and PPAR gamma in the process of osteoblast differentiation. Thus, PPAR alpha actions promote BMP-induced osteoblast differentiation, while both activities of PPAR alpha and PPAR gamma suppress TNF-alpha actions. Collectively, our present data establishes that PPAR activities are functionally involved in modulating the interaction between the BMP system and TNF-alpha receptor signaling that is crucial for bone metabolism.
キーワード
Bone morphogenetic protein (BMP)
Peroxisome proliferator-activated receptor (PPAR)
Osteoblast
Tumor necrosis factor-alpha (TNF-alpha)
発行日
2012-01-02
出版物タイトル
Molecular and Cellular Endocrinology
348巻
1号
開始ページ
224
終了ページ
232
ISSN
0303-7207
資料タイプ
学術雑誌論文
オフィシャル URL
http://dx.doi.org/10.1016/j.mce.2011.08.027
関連URL
http://ousar.lib.okayama-u.ac.jp/metadata/49131
言語
English
著作権者
(C) 2011 Elsevier Ireland Ltd. All rights reserved.
論文のバージョン
author
査読
有り
DOI
Web of Sience KeyUT