| First Author | Mukai T | Year | 2007 |
| Journal | Biochem Biophys Res Commun | Volume | 356 |
| Issue | 4 | Pages | 1004-10 |
| PubMed ID | 17397798 | Mgi Jnum | J:121620 |
| Mgi Id | MGI:3710736 | Doi | 10.1016/j.bbrc.2007.03.099 |
| Citation | Mukai T, et al. (2007) TNF-alpha inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling. Biochem Biophys Res Commun 356(4):1004-10 |
| abstractText | The cellular mechanism by which TNF-alpha inhibits osteoblastic differentiation induced by BMPs was investigated using mouse myoblast C2C12 cells expressing functional BMP receptors and Smad signaling molecules except ALK-6. Osteoblast transformation in response to BMP-2 was morphologically suppressed by TNF-alpha. Expression of biological markers for osteoblasts including Runx2 and osteocalcin, alkaline phosphatase activity, and parathyroid hormone (PTH) responsiveness shown by PTH-induced cAMP production were readily activated by BMP-2, -4, -6, and -7. The BMP-induced osteoblastic phenotype was dose-dependently inhibited by TNF-alpha. BMP-induced Smad1,5,8 phosphorylation of C2C12 cells was suppressed by TNF-alpha signaling. In addition, cDNA array analysis showed an increased expression of inhibitory Smad6 by TNF-alpha. MAP kinase analysis showed that ERK1/ERK2 and SAPK/JNK phosphorylation were selectively activated by TNF-alpha regardless of the presence of BMP ligands. BMPs had no effect on expression levels of TNF type 1 and 2 receptors. Notably, inhibition of SAPK/JNK restored TNF-alpha effects on BMP-induced osteoblast differentiation demonstrated by Id-1-promoter activity as well as Runx2 and osteocalcin mRNA levels. Collectively, TNF-alpha elicits BMP-induced osteogenic inhibition by suppressing BMP-Smad signaling pathway, at least in part, through SAPK/JNK activation and Smad6 upregulation. |
