Cyclic AMP response element-binding protein H (CREBH) mediates the inhibitory actions of tumor necrosis factor α in osteoblast differentiation by stimulating Smad1 Degradation

Won Gu Jang, Byung Chul Jeong, Eun Jung Kim, Hyuck Choi, Sin Hye Oh, Don Kyu Kim, Seung-Hoi Koo, Hueng Sik Choi, Jeong Tae Koh

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12 Citations (Scopus)


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 proteinH(CREBH), a member of the same family of ER membrane-bound basic leucine zipper (bZIP) transcription factors as OASIS and ATF6, in osteoblast differentiation and bone formation. Proinflammatory cytokineTNFα increased CREBH expression by up-regulating the nuclear fac-tor-kB (NF-kB) 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, whereas knockdownof CREBH inhibited TNF-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.

Original languageEnglish
Pages (from-to)13556-13566
Number of pages11
JournalJournal of Biological Chemistry
Issue number21
Publication statusPublished - 2015 May 22


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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