Osteopenia in transgenic mice with osteoblast-targeted expression of the inducible cAMP early repressor

Chandhoke, Taranpreet; Huang, Yu Feng; Liu, Fei; Gronowicz, Gloria; Adams, Douglas; Harrison, John; Kream, Barbara E.

doi:10.1016/j.bone.2008.03.012

Cited by 18 publications

(25 citation statements)

References 59 publications

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“…However, functional redundancy could be achieved in bone through other family of proteins able to form inactive heterodimers with ATF4. Candidates include ICER (Chandhoke et al, 2008) or other leucine zipper factors such as CHOP (CCAAT/Enhancer-binding protein Homologous Protein) (Pereira et al, 2007). It is also possible that a stronger phenotype could be detected in older mice.…”

Section: Discussionmentioning

confidence: 99%

Altered gene dosage confirms the genetic interaction between FIAT and αNAC

Hekmatnejad¹,

Mandic²,

Yu³

et al. 2014

Gene

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Factor inhibiting ATF4-mediated transcription (FIAT) interacts with Nascent polypeptide associated complex And coregulator alpha (αNAC). In cultured osteoblastic cells, this interaction contributes to maximal FIAT-mediated inhibition of Osteocalcin (Ocn) gene transcription. We set out to demonstrate the physiological relevance of this interaction by altering gene dosage in compound Fiat and Naca (encoding αNAC) heterozygous mice. Compound Naca+/−; Fiat+/− heterozygous animals were viable, developed normally, and exhibited no significant difference in body weight compared with control littermate genotypes. Animals with a single Fiat allele had reduced Fiat mRNA expression without changes in the expression of related family members. Expression of the osteocyte differentiation marker Dmp1 was elevated in compound heterozygotes. Static histomorphometry parameters were assessed at 8 weeks of age using microcomputed tomography (μCT). Trabecular measurements were not different between genotypes. Cortical thickness and area were not affected by gene dosage, but we measured a significant increase in cortical porosity in compound heterozygous mice, without changes in biomechanical parameters. The bone phenotype of compound Naca+/−; Fiat+/− heterozygotes confirms that FIAT and αNAC are part of a common genetic pathway and support a role for the FIAT/αNAC interaction in normal bone physiology.

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Section: Discussionmentioning

confidence: 99%

Altered gene dosage confirms the genetic interaction between FIAT and αNAC

Hekmatnejad¹,

Mandic²,

Yu³

et al. 2014

Gene

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“…The anabolic function of this cAMP-PKA-CREB pathway in bone has been characterized in vivo and in vitro [11]–[30]. Increasing activity of this pathway promotes osteoblast differentiation [11]–[26] and stimulates bone formation [27]–[30].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation of BMP2 Expression by the PTH-CREB Signaling Pathway in Osteoblasts

Zhang

Edwards

et al. 2011

PLoS ONE

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Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts.

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“…The bZIP transcriptional repressor ICER (inducible cAMP early repressor), a CRE modulator (CREM) isoform, antagonizes the activity of ATF4, presumably through protein-protein interaction via the leucine zipper [Chandhoke et al, 2008]. The formation of inactive heterodimers was also characterized as a significant mechanism explaining the regulation of ATF4 activity by the leucine zipper containing protein FIAT [Yu et al, 2005].…”

Section: Fiat In Osteoblasts Journal Of Cellular Biochemistrymentioning

confidence: 98%

“…Yu, and R. St-Arnaud, unpublished). However, functional redundancy (i.e., control of ATF4 activity through formation of inactive heterodimers) could be achieved in bone through expression of ICER [Chandhoke et al, 2008], or other OSE2 (osteoblast-specific element 2) which is the binding site for RUNX2. B: Interaction of ATF4 with FIAT forms inactive dimers that cannot bind the OSE1 site.…”

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confidence: 99%

FIAT control of osteoblast activity

St‐Arnaud¹,

Mandic²

2009

J of Cellular Biochemistry

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The basic domain-leucine zipper transcription factor activating transcription factor 4 (ATF4) regulates most functions of the osteoblast. It is therefore not surprising that its activity should be regulated through several mechanisms. Factor inhibiting ATF4-mediated transcription (FIAT) is a leucine zipper nuclear molecule lacking a basic domain for DNA binding that interacts with ATF4 to repress its transcriptional activity. FIAT expression was monitored in parallel with ATF4 during osteoblastogenesis. The mechanism of ATF4 repression by FIAT was investigated through structure-function analysis. The physiological significance of FIAT expression in osteoblasts was studied through silencing FIAT in osteoblasts by RNA interference, as well as through characterization of two genetic mouse models: FIAT transgenic mice which overexpress FIAT in osteoblasts, and FIAT knockout mice. Studies to date show that FIAT and ATF4 are co-expressed in osteoblasts, and that FIAT inhibition of matrix mineralization requires dimerization with ATF4 through the second leucine zipper. Furthermore, transgenic mice overexpressing FIAT exhibit osteopenia. The phenotype of FIAT knockout mice is still under evaluation but the salient aspects are discussed here. Taken together, the results accumulated to date support the hypothesis that FIAT is a transcriptional repressor that modulates osteoblast function.

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Osteopenia in transgenic mice with osteoblast-targeted expression of the inducible cAMP early repressor

Cited by 18 publications

References 59 publications

Altered gene dosage confirms the genetic interaction between FIAT and αNAC

Altered gene dosage confirms the genetic interaction between FIAT and αNAC

Transcriptional Regulation of BMP2 Expression by the PTH-CREB Signaling Pathway in Osteoblasts

FIAT control of osteoblast activity

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