TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling

Tomoyuki Mukai, Fumio Otsuka, Hiroyuki Otani, Misuzu Yamashita, Koji Takasugi, Kenichi Inagaki, Masahiro Yamamura, Hirofumi Makino

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

The cellular mechanism by which TNF-α 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-α. 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-α. BMP-induced Smad1,5,8 phosphorylation of C2C12 cells was suppressed by TNF-α signaling. In addition, cDNA array analysis showed an increased expression of inhibitory Smad6 by TNF-α. MAP kinase analysis showed that ERK1/ERK2 and SAPK/JNK phosphorylation were selectively activated by TNF-α 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-α effects on BMP-induced osteoblast differentiation demonstrated by Id-1-promoter activity as well as Runx2 and osteocalcin mRNA levels. Collectively, TNF-α elicits BMP-induced osteogenic inhibition by suppressing BMP-Smad signaling pathway, at least in part, through SAPK/JNK activation and Smad6 upregulation.

Original languageEnglish
Pages (from-to)1004-1010
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume356
Issue number4
DOIs
Publication statusPublished - May 18 2007

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Keywords

  • Bone morphogenetic protein (BMP)
  • C2C12
  • Mitogen-activated protein (MAP) kinase
  • Osteoblast
  • Tumor necrosis factor (TNF)-α

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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