FIAT inhibition increases osteoblast activity by modulating Atf4‐dependent functions

Yu, Vionnie W.C.; El-Hoss, Jad; St‐Arnaud, René

doi:10.1002/jcb.21995

Cited by 11 publications

(16 citation statements)

References 26 publications

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“…To unravel the cellular mechanisms that account for the high bone mass, we undertook differentiation studies of cultured primary osteoblasts derived from mice long bones. Consistent with the in vitro phenotype in which FIAT expression was inhibited using short hairpin RNA-mediated knockdown in MC3T3-E1 osteoblastic cells (17), primary osteoblast cultures obtained from Fiat −/Y mice demonstrated increased mineralization and increased expression of both early and late osteoblast-specific markers ( Runx2 , Alpl , and Bglap ). Reciprocally, adipogenic differentiation of Fiat -deficient BMSCs was reduced.…”

Section: Discussionsupporting

confidence: 63%

“…Because transgenic mice overexpressing FIAT are osteopenic, we hypothesized that, inversely, inhibition of FIAT would augment ATF4 function and lead to increased osteoblast activity. This hypothesis was validated in tissue culture using small interfering RNA-mediated knockdown of FIAT, which resulted in increased osteocalcin ( Bglap ) gene transcription, type I collagen synthesis, and mineralization (17). To gain further evidence of the regulatory role of FIAT in vivo , we engineered mice deficient for Fiat .…”

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confidence: 94%

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FIAT deletion increases bone mass but does not prevent high-fat-diet-induced metabolic complications

Hekmatnejad

Addison

et al. 2016

Endocrinology

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Factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT) interacts with ATF4 to repress its transcriptional activity. We performed a phenotypic analysis of Fiat-deficient male mice (Fiat−/Y) at 8 and 16 weeks of age. Microcomputed tomography analysis of the distal femur demonstrated 46% and 13% age-dependent increases in trabecular bone volume and thickness, respectively, in Fiat−/Y mice. Cortical bone measurements at the femoral midshaft revealed a substantial increase in cortical thickness in older Fiat−/Y mice. Bone gain was related to increased mineral apposition rate and increased osteoblast function. Femoral stiffness and strength were substantially increased in Fiat−/Y compared with wild-type (WT) mice. We also investigated whether FIAT contributes to metabolic function. When fed standard mouse chow, Fiat−/Y animals were glucose-tolerant. However, when fed a high-fat diet (HFD) for 8 weeks, Fiat−/Y mice gained more weight than control mice, with a specific increase in white adipose tissue fat mass. The increase in fat mass was due to reduced energy expenditure, which correlated with reduced fatty acid oxidation and lipolysis in the adipose tissue of mutant mice. The expression of the Scd1 gene, involved in lipogenesis, was upregulated in the subcutaneous adipose tissue of Fiat−/Y mice. Moreover, HFD-fed Fiat−/Y mice exhibited increased circulating leptin and insulin levels relative to WT mice, demonstrating that endocrine abnormalities are associated with the disturbance in energy balance. We conclude that Fiat−/Y mice exhibited an anabolic bone phenotype but displayed increased susceptibility to developing metabolic-related disorders when consuming an HFD.

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Section: Discussionsupporting

confidence: 63%

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confidence: 94%

FIAT deletion increases bone mass but does not prevent high-fat-diet-induced metabolic complications

Hekmatnejad

Addison

et al. 2016

Endocrinology

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“…It is unlikely that this was observed because FIAT does not modulate this ATF4 function since FIAT knockdown in cultured osteoblasts impacted on the synthesis of type I collagen [Yu et al, 2009b]. Most likely, the unaffected type I collagen synthesis in FIAT transgenic bones was caused by the relatively moderate overexpression of the FIAT transgene (estimated at 20% above endogenous) achieved in this model system [Yu et al, 2005].…”

Section: Fiat Activity In Vivomentioning

confidence: 85%

“…Indeed, stable overexpression of a FIAT transgene inhibits transcription from the Osteocalcin gene promoter and reduces mineralization, both in primary osteoblasts cultures or in an osteoblastic cell line [Yu et al, 2005[Yu et al, , 2008b. Conversely, siRNA-mediated knockdown of FIAT expression enhanced all ATF4 functions tested: Osteocalcin transcription and promoter occupancy, bone sialoprotein (Bsp) gene transcription, as well as type I collagen synthesis [Yu et al, 2009b]. FIAT-knockdown osteoblasts also displayed increased mineralization and an increased number of nodules [Yu et al, 2009b].…”

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confidence: 96%

“…Conversely, siRNA-mediated knockdown of FIAT expression enhanced all ATF4 functions tested: Osteocalcin transcription and promoter occupancy, bone sialoprotein (Bsp) gene transcription, as well as type I collagen synthesis [Yu et al, 2009b]. FIAT-knockdown osteoblasts also displayed increased mineralization and an increased number of nodules [Yu et al, 2009b].In a parallel line of investigation, it was observed that FIAT can repress the transcriptional activity of the FRA-1/cJUN heterodimer [St-Arnaud and Elchaarani, 2007]. Since FIAT does not affect cJUN function [St-Arnaud and Elchaarani, 2007], the logical conclusion is that FIAT specifically inhibits FRA-1 activity.…”

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confidence: 98%

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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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Control of Fiat (factor inhibiting ATF4‐mediated transcription) expression by Sp family transcription factors in osteoblasts

Hekmatnejad

Gauthier

St‐Arnaud

2013

J of Cellular Biochemistry

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FIAT (factor inhibiting ATF4-mediated transcription) represses Osteocalcin gene transcription and inhibits osteoblast activity by heterodimerizing with ATF4 to prevent it from binding DNA. It thus appears important to identify and characterize the molecular mechanisms that control Fiat gene expression in osteoblasts. In silico sequence analysis identified a canonical GC-box within a 1,400 bp region of the proximal Fiat gene promoter. Electrophoretic mobility shift assays (EMSA) with MC3T3-E1 osteoblastic cells nuclear extracts indicated that the transcription factors Sp1 and Sp3, but not Sp7/OSTERIX, bound this proximal GC-box. Chromatin immunoprecipitation confirmed interaction of the two transcription factors with the Fiat promoter GC-element in living osteoblasts. Transient transfection studies showed that Sp1 dose-dependently activated the expression of a Fiat-luciferase reporter construct while both the long or short isoforms of Sp3 dose-dependently inhibited transcription from the Fiat reporter construct. Transfection of an Sp7/OSTERIX expression vector did not affect expression of the Fiat-luciferase reporter. Co-transfection of increasing amounts of the Sp3 expression vector in the context of maximal Sp1-dependent Fiat-luciferase activation led to dose-dependent repression of the expression of the reporter. Using RNA knockdown, we measured a reduction in steady-state Fiat expression when Sp1 was inhibited, and a reciprocal increase upon Sp3 knockdown. In parallel, treatment of osteoblasts with WP631, which prevents Sp1/DNA interactions, strongly inhibited the expression of Fiat and reduced the occupancy of the Fiat promoter proximal GC-box by Sp1. Taken together, our results suggest an interplay between Sp1 and Sp3 as a mechanism involved in the control of Fiat gene expression in osteoblasts.

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FIAT inhibition increases osteoblast activity by modulating Atf4‐dependent functions

Cited by 11 publications

References 26 publications

FIAT deletion increases bone mass but does not prevent high-fat-diet-induced metabolic complications

FIAT deletion increases bone mass but does not prevent high-fat-diet-induced metabolic complications

FIAT control of osteoblast activity

Control of Fiat (factor inhibiting ATF4‐mediated transcription) expression by Sp family transcription factors in osteoblasts

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