Peroxisome proliferator-activated receptor activity is involved in the osteoblastic differentiation regulated by bone morphogenetic proteins and tumor necrosis factor-¦Á

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• 作者：Mariko Takano ; Fumio Otsuka  ; ;   ; ^{fumiotsu@md.okayama-u.ac.jp} ; Yoshinori Matsumoto ; Kenichi Inagaki ; Masaya Takeda ; Eri Nakamura ; Naoko Tsukamoto ; Tomoko Miyoshi ; Ken-ei Sada ; Hirofumi Makino
• 关键词：Bone morphogenetic protein (BMP) ; Peroxisome proliferator-activated receptor (PPAR) ; Osteoblast ; Tumor necrosis factor-¦Á (TNF-¦Á)
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2012
• 出版时间：2 January 2012
• 年：2012
• 卷：348
• 期：1
• 页码：224-232
• 全文大小：1432 K

文摘

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-¦Á 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¦Á agonist (fenofibric acid) but not with a PPAR¦Ã agonist (pioglitazone), BMP-4 enhanced osteoblast differentiation through the activity of PPAR¦Á. The osteoblastic changes induced by BMP-4 were readily suppressed by treatment with TNF-¦Á. Interestingly, the activities of PPAR¦Á and PPAR¦Ã agonists reversed the suppression by TNF-¦Á of osteoblast differentiation induced by BMP-4. Furthermore, TNF-¦Á-induced phosphorylation of MAPKs, NF¦ÊB, I¦ÊB and Stat pathways was inhibited in the presence of PPAR¦Á and PPAR¦Ã agonists with reducing TNF-¦Á receptor expression. In view of the finding that inhibition of SAPK/JNK, Stat and NF¦ÊB pathways reversed the TNF-¦Á suppression of osteoblast differentiation, we conclude that these cascades are functionally involved in the actions of PPARs that antagonize TNF-¦Á-induced suppression of osteoblast differentiation. It was further discovered that the PPAR¦Á agonist enhanced BMP-4-induced Smad1/5/8 signaling through downregulation of inhibitory Smad6/7 expression, whereas the PPAR¦Ã agonist impaired this activity by suppressing BMPRII expression. On the other hand, BMPs increased the expression levels of PPAR¦Á and PPAR¦Ã in the process of osteoblast differentiation. Thus, PPAR¦Á actions promote BMP-induced osteoblast differentiation, while both activities of PPAR¦Á and PPAR¦Ã suppress TNF-¦Á actions. Collectively, our present data establishes that PPAR activities are functionally involved in modulating the interaction between the BMP system and TNF-¦Á receptor signaling that is crucial for bone metabolism.