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

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

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
Volume290
Issue number21
DOIs
Publication statusPublished - 2015 May 22

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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