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.
Highlights
TNF-α is a proinflammatory cytokine that plays an important role in various physiological and pathological processes including cell death, growth, differentiation and inflammation (Chen and Goeddel, 2002; Wajant et al, 2003)
We showed that TNF-α induces Msx2 expression in C2C12 cells through NF-κB activation, which in turn inhibits bone morphogenetic protein 2 (BMP2)-induced expression of alkaline phosphatase (ALP)
We first examined the effect of TNF-α on BMP2-induced osteoblast differentiation
Summary
TNF-α is a proinflammatory cytokine that plays an important role in various physiological and pathological processes including cell death, growth, differentiation and inflammation (Chen and Goeddel, 2002; Wajant et al, 2003). There is a long-standing interest in the role of TNF-α because of its association with osteoporosis and rheumatoid arthritis. TNF-α decreases osteoblastic bone formation through the promotion of osteoblast apoptosis, the inhibition of osteoblast differentiation and the suppression of the matrix protein expression such as osteocalcin by mature osteoblasts (Kuno et al, 1994; Kitajima et al, 1996; Nakase et al, 1997; Gilbert et al, 2000, 2002). TNF-α decreases both the mRNA and protein levels of Runx via the suppression of transcription, destabilization of mRNA, and enhanced degradation of Runx protein (Gilbert et al, 2002; Kaneki et al, 2006). The inhibitory roles of TNF-α in osteoblast differentiation have been described, the detailed TNF-α signaling pathways involved remain unclear
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