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 journalArticle

11 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

Fingerprint

Cyclic AMP Response Element-Binding Protein
Osteoblasts
Bone Morphogenetic Protein 2
Tumor Necrosis Factor-alpha
Degradation
Osteogenesis
Activating Transcription Factor 6
Bone
Ubiquitination
Osteocalcin
Astrocytes
Alkaline Phosphatase
Basic-Leucine Zipper Transcription Factors
Endoplasmic Reticulum Stress
Response Elements
Ubiquitin
Transducers
Gene expression
Endoplasmic Reticulum
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cyclic AMP response element-binding protein H (CREBH) mediates the inhibitory actions of tumor necrosis factor α in osteoblast differentiation by stimulating Smad1 Degradation. / Jang, Won Gu; Jeong, Byung Chul; Kim, Eun Jung; Choi, Hyuck; Oh, Sin Hye; Kim, Don Kyu; Koo, Seung-Hoi; Choi, Hueng Sik; Koh, Jeong Tae.

In: Journal of Biological Chemistry, Vol. 290, No. 21, 22.05.2015, p. 13556-13566.

Research output: Contribution to journalArticle

Jang, Won Gu ; Jeong, Byung Chul ; Kim, Eun Jung ; Choi, Hyuck ; Oh, Sin Hye ; Kim, Don Kyu ; Koo, Seung-Hoi ; Choi, Hueng Sik ; Koh, Jeong Tae. / Cyclic AMP response element-binding protein H (CREBH) mediates the inhibitory actions of tumor necrosis factor α in osteoblast differentiation by stimulating Smad1 Degradation. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 21. pp. 13556-13566.
@article{995c34aa3e69446f99c151489f66f29f,
title = "Cyclic AMP response element-binding protein H (CREBH) mediates the inhibitory actions of tumor necrosis factor α in osteoblast differentiation by stimulating Smad1 Degradation",
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.",
author = "Jang, {Won Gu} and Jeong, {Byung Chul} and Kim, {Eun Jung} and Hyuck Choi and Oh, {Sin Hye} and Kim, {Don Kyu} and Seung-Hoi Koo and Choi, {Hueng Sik} and Koh, {Jeong Tae}",
year = "2015",
month = "5",
day = "22",
doi = "10.1074/jbc.M114.587923",
language = "English",
volume = "290",
pages = "13556--13566",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "21",

}

TY - JOUR

T1 - Cyclic AMP response element-binding protein H (CREBH) mediates the inhibitory actions of tumor necrosis factor α in osteoblast differentiation by stimulating Smad1 Degradation

AU - Jang, Won Gu

AU - Jeong, Byung Chul

AU - Kim, Eun Jung

AU - Choi, Hyuck

AU - Oh, Sin Hye

AU - Kim, Don Kyu

AU - Koo, Seung-Hoi

AU - Choi, Hueng Sik

AU - Koh, Jeong Tae

PY - 2015/5/22

Y1 - 2015/5/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84930008877&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930008877&partnerID=8YFLogxK

U2 - 10.1074/jbc.M114.587923

DO - 10.1074/jbc.M114.587923

M3 - Article

C2 - 25873397

AN - SCOPUS:84930008877

VL - 290

SP - 13556

EP - 13566

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -