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 protein H (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 cytokine TNFα increased CREBH expression by up-regulating the nuclear factor-κB (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 up-regulation 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 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.
authors: From the Research Center for Biomineralization Disorders, Department of Pharmacology and Dental Therapeutics, School of Dentistry, and the Department of Biotechnology, School of Engineering, Daegu University, Gyeongsan 712-714, and.
authors: Won-Gu
authors: WG
authors: Jang
authors: From the Research Center for Biomineralization Disorders, Department of Pharmacology and Dental Therapeutics, School of Dentistry, and.
authors: Byung-Chul
authors: BC
authors: Jeong
authors: From the Research Center for Biomineralization Disorders, Department of Pharmacology and Dental Therapeutics, School of Dentistry, and.
authors: Eun-Jung
authors: EJ
authors: Kim
authors: From the Research Center for Biomineralization Disorders, Department of Pharmacology and Dental Therapeutics, School of Dentistry, and.
authors: Hyuck
authors: H
authors: Choi
authors: From the Research Center for Biomineralization Disorders, Department of Pharmacology and Dental Therapeutics, School of Dentistry, and.
authors: Sin-Hye
authors: SH
authors: Oh
authors: the National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757.
authors: Don-Kyu
authors: DK
authors: Kim
authors: the Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul-136-701, Republic-of-Korea.
authors: Seung-Hoi
authors: SH
authors: Koo
authors: the National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, hsc@chonnam.ac.kr.
authors: Hueng-Sik
authors: HS
authors: Choi
authors: From the Research Center for Biomineralization Disorders, Department of Pharmacology and Dental Therapeutics, School of Dentistry, and jtkoh@chonnam.ac.kr.
authors: Jeong-Tae
authors: JT
authors: Koh
mesh_terms: D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D055396:Bone Morphogenetic Protein 2; C533813:CREB3L3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D051898:Smad1 Protein; D014409:Tumor Necrosis Factor-alpha; D000469:Alkaline Phosphatase
keywords: SMAD transcription factor; cAMP response element-binding protein (CREB); endoplasmic reticulum stress (ER stress); osteoblast; tumor necrosis factor (TNF)