| First Author | Takano M | Year | 2012 |
| Journal | Mol Cell Endocrinol | Volume | 348 |
| Issue | 1 | Pages | 224-32 |
| PubMed ID | 21888945 | Mgi Jnum | J:184104 |
| Mgi Id | MGI:5320258 | Doi | 10.1016/j.mce.2011.08.027 |
| Citation | Takano M, et al. (2012) Peroxisome proliferator-activated receptor activity is involved in the osteoblastic differentiation regulated by bone morphogenetic proteins and tumor necrosis factor-alpha. Mol Cell Endocrinol 348(1):224-32 |
| abstractText | 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 PPARalpha agonist (fenofibric acid) but not with a PPARgamma agonist (pioglitazone), BMP-4 enhanced osteoblast differentiation through the activity of PPARalpha. The osteoblastic changes induced by BMP-4 were readily suppressed by treatment with TNF-alpha. Interestingly, the activities of PPARalpha and PPARgamma agonists reversed the suppression by TNF-alpha of osteoblast differentiation induced by BMP-4. Furthermore, TNF-alpha-induced phosphorylation of MAPKs, NFkappaB, IkappaB and Stat pathways was inhibited in the presence of PPARalpha and PPARgamma agonists with reducing TNF-alpha receptor expression. In view of the finding that inhibition of SAPK/JNK, Stat and NFkappaB 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 PPARalpha agonist enhanced BMP-4-induced Smad1/5/8 signaling through downregulation of inhibitory Smad6/7 expression, whereas the PPARgamma agonist impaired this activity by suppressing BMPRII expression. On the other hand, BMPs increased the expression levels of PPARalpha and PPARgamma in the process of osteoblast differentiation. Thus, PPARalpha actions promote BMP-induced osteoblast differentiation, while both activities of PPARalpha and PPARgamma 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. |
