Msx2 mediates the inhibitory action of TNF-alpha on osteoblast differentiation.
10.3858/emm.2010.42.6.045
- Author:
Hye Lim LEE
1
;
TacGhee YI
;
Kyung Mi WOO
;
Hyun Mo RYOO
;
Gwan Shik KIM
;
Jeong Hwa BAEK
Author Information
1. Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Korea. baekjh@snu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
alkaline phosphatase;
bone morphogenetic protein 2;
cell differentiation;
Msx2 protein;
NF-kappaB;
osteoblasts;
tumor necrosis factor-alpha
- MeSH:
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
- From:Experimental & Molecular Medicine
2010;42(6):437-445
- CountryRepublic of Korea
- Language:English
-
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.
