Cyclic AMP response element-binding protein H (CREBH) Mediates the Inhibitory Actions of Tumor Necrosis Factor {alpha} in Osteoblast Differentiation by Stimulating Smad1 Degradation [Signal Transduction]

April 14th, 2015 by Jang, W.-G., Jeong, B.-C., Kim, E.-J., Choi, H., Oh, S.-H., Kim, D.-K., Koo, S.-H., Choi, H.-S., Koh, J.-T.

Endoplasmic reticulum (ER) stress transducers, such as old astrocyte specifically induced substance (OASIS) and activating transcription factor 6 (ATF6), which are induced by bone morphogenetic protein 2 (BMP2), regulate bone formation and osteoblast differentiation. Here, we examined the role of cAMP response element-binding protein H (CREBH), a member of the same family of ER membrane-bound bZIP transcription factors as OASIS and ATF6, in osteoblast differentiation and bone formation. Proinflammatory TNFα increased CREBH expression by upregulating the nuclear factor-kappa B (NF-κB) signaling pathway in osteoblasts, increased the level of N-terminal fragment of CREBH in the nucleus, and inhibited BMP2 induction of osteoblast specific gene expression. Overexpression of CREBH suppressed BMP2-induced upregulation of the osteogenic markers runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and osteocalcin (OC) in MC3T3-E1 cells and primary osteoblasts, as well as BMP2-induced ALP activity and OC protein production. In contrast, knockdown of CREBH attenuated the inhibitory effect of TNFα on BMP2-induced osteoblast differentiation. Mechanistic studies revealed that CREBH increased the expression of Smad ubiquitination regulatory factor 1 (Smurf1), leading to ubiquitin-dependent degradation of Smad1, while knockdown of CREBH inhibited TNFα-mediated degradation of Smad1 by Smurf1. Consistent with these in vitro findings, administration of Ad-CREBH inhibited BMP2-induced ectopic and orthotopic bone formation in vivo. Taken together, these results suggest that CREBH is a novel negative regulator of osteoblast differentiation and bone formation.
  • Posted in Journal of Biological Chemistry, Publications
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