BMP2 Protein Regulates Osteocalcin Expression via Runx2-mediated Atf6 Gene Transcription

Jang, Won Gu; Kim, Eun Jung; Kim, Don-Kyu; Ryoo, Hyun‐Mo; Lee, Keun-Bae; Kim, Sun-Hun; Choi, Hueng‐Sik; Koh, Jeong‐Tae

doi:10.1074/jbc.m111.253187

Cited by 184 publications

(139 citation statements)

References 39 publications

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“…In addition, BMP2 increased the levels of the Smad1, Runx2, and ATF6 proteins in osteoblasts (Fig. 5G), as described previously (32,45), and overexpression of CREBH attenuated these BMP2 effects with the increased Smurf1 level. These indicate that TNF␣ may suppress BMP2-induced osteoblast differentiation through the CREBH/Smurf/ Smad1 regulatory system.…”

Section: Discussionmentioning

confidence: 63%

“…OASIS Ϫ/Ϫ mice exhibit severe osteopenia with reduced levels of collagen type ␣I in the bone matrix and reduced activity of osteoblasts (9). In our previous study, ATF6 stimulated osteoblast differentiation by regulating osteocalcin gene expression directly (32). However, the mechanisms involved in the sensing of unfolded proteins and translocation from the ER to the Golgi differ between OASIS family members.…”

Section: Discussionmentioning

confidence: 97%

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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

Jeong²,

Kim³

et al. 2015

Journal of Biological Chemistry

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Background: Severe inflammatory reactions delay wound healing of bone. Results: Tumor necrosis factor ␣ (TNF␣) inhibition of osteoblast differentiation is associated with increased cAMP response element-binding protein H (CREBH) and Smurf1 expression. Conclusion: CREBH mediates the inhibitory actions of TNF␣ in bone regeneration. Significance: CREBH is identified as a new mediator of inflammation-dependent bone degradation and a potential therapeutic target.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 97%

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

Jeong²,

Kim³

et al. 2015

Journal of Biological Chemistry

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“…Initially vibration upregulates expression of the osteoblast-specific master gene, Runx2, which leads to increased Osterix expression as the cells differentiate into osteoblast precursors. Runx2 and Osterix transcription factors may regulate subsequent extracellular matrix gene transcription, such as ALP, Col1, BSP, OPN, and OC (Harada et al 1999;Jang et al 2012;Javed et al 2001;Welch et al 1998). Immature osteoblasts then differentiate into mature osteoblasts through matrix production and mineralization (Eriksen 2010).…”

Section: Discussionmentioning

confidence: 99%

Vibrational stimulation induces osteoblast differentiation and the upregulation of osteogenic gene expression in vitro

2016

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Vibrational stimulation is an accepted non-invasive method used to improve bone remodeling. However, the underlying mechanisms of this phenomenon remain unclear. In this study, we developed a new vibration-loading system to apply vibrational stimulation to cells based on a previously reported in vivo study. We hypothesized that osteoblasts respond to vibrational strain by expressing osteogenic marker genes, such as alkaline-phosphatase (ALP), Runx2, and Osterix. To test our hypothesis, we developed a vibration-loading system to apply a precise vibrational force to an osteoblast culture on a silicone membrane. The system regulated frequency and acceleration of the vibration, and strain on the silicone membrane culture surface was measured using the strain gauge method. After vibrational stimulation, cellular gene expression was analyzed using real-time polymerase chain reaction. We obtained clear strain signals from the culture surface at vibrational ranges of 1.0-10 m/s 2 acceleration and frequencies of 30, 60, and 90 Hz, respectively. The strain increased in a linear fashion, depending on the acceleration magnitude. Vibrational stimulation also significantly upregulated expression of the osteogenic marker genes Runx2, Osterix, type I collagen, and ALP. In conclusion, we developed a new vibrationloading system that can precisely regulate frequency and acceleration, and we established the presence of dynamic cellular strain on a culture surface. Our findings suggest that vibrational stimulation may directly induce osteoblast differentiation.

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“…Treatment of precursor osteoblasts with bone morphogenetic protein BMP2 is suggested to activate each of the UPR branches, directing expression of target genes that contribute to secretion and bone formation (13,14,16). Given the central role of the UPR in protein homeostasis and expansion of secretory capacity, there is a growing consensus that the UPR functions in conjunction with additional regulators of bone development.…”

mentioning

confidence: 99%

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

Young¹,

Shao

Bidwell

et al. 2016

Journal of Biological Chemistry

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The unfolded protein response (UPR) maintains protein homeostasis by governing the processing capacity of the endoplasmic reticulum (ER) to manage ER client loads; however, key regulators within the UPR remain to be identified. Activation of the UPR sensor PERK (EIFAK3/PEK) results in the phosphorylation of the ␣ subunit of eIF2 (eIF2␣-P), which represses translation initiation and reduces influx of newly synthesized proteins into the overloaded ER. As part of this adaptive response, eIF2␣-P also induces a feedback mechanism through enhanced transcriptional and translational expression of Gadd34 (Ppp1r15A), which targets type 1 protein phosphatase for dephosphorylation of eIF2␣-P to restore protein synthesis. Here we describe a novel mechanism by which Gadd34 expression is regulated through the activity of the zinc finger transcription factor NMP4 (ZNF384, CIZ). NMP4 functions to suppress bone anabolism, and we suggest that this occurs due to decreased protein synthesis of factors involved in bone formation through NMP4-mediated dampening of Gadd34 and c-Myc expression. Loss of Nmp4 resulted in an increase in c-Myc and Gadd34 expression that facilitated enhanced ribosome biogenesis and global protein synthesis. Importantly, protein synthesis was sustained during pharmacological induction of the UPR through a mechanism suggested to involve GADD34-mediated dephosphorylation of eIF2␣-P. Sustained protein synthesis sensitized cells to pharmacological induction of the UPR, and the observed decrease in cell viability was restored upon inhibition of GADD34 activity. We conclude that NMP4 is a key regulator of ribosome biogenesis and the UPR, which together play a central role in determining cell viability during endoplasmic reticulum stress.Professional secretory cells balance the synthesis, folding, and trafficking of proteins to ensure optimal protein export.Upon differentiation and physiological cues, increased synthesis of polypeptides slated for secretion can lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) 3 that trigger the unfolded protein response (UPR) (1). The UPR features multiple sensory proteins, including PERK (EIF2AK3/ PEK), IRE1 (ERN1), and ATF6, which are each situated in the ER and are activated by unfolded proteins in the ER (1). Induction of the UPR leads to a program of translational and transcriptional gene expression that collectively serve to expand the processing capacity of the ER to effectively manage an expanded ER client load (1).In response to ER stress, PERK phosphorylates the ␣ subunit of eIF2 (eIF2␣-P), which represses global translation initiation that reduces influx of newly synthesized proteins into the overloaded ER (2, 3). Coincident with dampening of global protein synthesis, eIF2␣-P leads to preferential translation of Atf4, encoding a transcription activator of UPR genes involved in nutrient import, metabolism, and alleviation of oxidative stress (4 -6). ATF4 also directly induces the transcriptional expression of Gadd34 (Ppp1r15A), which targets ty...

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BMP2 Protein Regulates Osteocalcin Expression via Runx2-mediated Atf6 Gene Transcription

Cited by 184 publications

References 39 publications

Cyclic AMP Response Element-binding Protein H (CREBH) Mediates the Inhibitory Actions of Tumor Necrosis Factor α in Osteoblast Differentiation by Stimulating Smad1 Degradation

Cyclic AMP Response Element-binding Protein H (CREBH) Mediates the Inhibitory Actions of Tumor Necrosis Factor α in Osteoblast Differentiation by Stimulating Smad1 Degradation

Vibrational stimulation induces osteoblast differentiation and the upregulation of osteogenic gene expression in vitro

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

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