Exp Mol Med.  2010 Jun;42(6):437-445. 10.3858/emm.2010.42.6.045.

Msx2 mediates the inhibitory action of TNF-alpha on osteoblast differentiation

• Lee HL
• Yi T
• Woo KM
• Ryoo HM
• Kim GS
• Baek JH

• KMID: 1078359
• DOI: http://doi.org/10.3858/emm.2010.42.6.045

Abstract

TNF-alpha, a proinflammatory cytokine, inhibits osteoblast differentiation under diverse inflammatory conditions; however, the underlying mechanisms in terms of the TNF-alpha signaling pathway remain unclear. In this study, we examined the role of Msx2 in TNF-alpha-mediated inhibition of alkaline phosphatase (ALP) expression and the signaling pathways involved. TNF-alpha down-regulated ALP expression induced by bone morphogenetic protein 2 (BMP2) in C2C12 and Runx2-/- calvarial cells. Over-expression of Msx2 suppressed BMP2-induced ALP expression. Furthermore, TNF-alpha induced Msx2 expression, and the knockdown of Msx2 by small interfering RNAs rescued ALP expression, which was inhibited by TNF-alpha. TNF-alpha activated the NF-kappaB and the JNK pathways. Inhibition of NF-kappaB or JNK activation reduced the inhibitory effect of TNF-alpha on ALP expression, whereas TNF-alpha-induced Msx2 expression was only suppressed by the inhibition of the NF-kappaB pathway. Taken together, these results indicate that Msx2 mediates the inhibitory action of TNF-alpha on BMP2-regulated osteoblast differentiation and that the TNF-alpha-activated NF-kappaB pathway is responsible for Msx2 induction.

Keyword

alkaline phosphatase; bone morphogenetic protein 2; cell differentiation; Msx2 protein; NF-kappaB; osteoblasts; tumor necrosis factor-alpha

MeSH Terms

Alkaline Phosphatase/genetics/metabolism
Animals
Animals, Newborn
Bone Morphogenetic Protein 2/pharmacology
Cell Culture Techniques
Cell Differentiation/*drug effects/genetics
Cell Proliferation/drug effects
Cells, Cultured
Core Binding Factor Alpha 1 Subunit/genetics
Down-Regulation/drug effects
Gene Expression Regulation/drug effects
Homeodomain Proteins/antagonists & inhibitors/genetics/*physiology
Mice
Mice, Inbred ICR
Mice, Transgenic
Osteoblasts/*drug effects/metabolism/physiology
RNA, Small Interfering/pharmacology
Tumor Necrosis Factor-alpha/*pharmacology