Regulating ΔFosB expression in adult tet-off-ΔFosB transgenic mice alters bone formation and bone mass

Sims, Natalie A.; Sabatakos, G.; Chen, J.-S.; Kelz, Max B.; Nestler, Eric J.; Baron, Roland

doi:10.1016/s8756-3282(01)00622-6

Cited by 24 publications

(26 citation statements)

References 26 publications

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“…In vivo, an inverse relationship between the number of osteoblasts and bone marrow adipocytes has been demonstrated in several forms of osteopenia, where decreased bone mass is often associated with increased adipogenesis (6,29,57,60). Conversely, we have reported an osteosclerotic phenotype accompanied by decreased adipogenesis in transgenic mice that overexpress the AP-1 transcription factor ⌬FosB under the control of the NSE promoter (25,47,53).…”

Section: Discussionmentioning

confidence: 76%

“…We have recently reported that transgenic mice overexpressing ⌬FosB, a member of the activator protein 1 (AP-1) family of transcription factors, under the control of the neuron-specific enolase (NSE) promoter develop not only a severe and progressive osteosclerotic phenotype, characterized as increased bone formation, but also a pronounced decrease in adipogenesis and fat levels (25,47,53). The AP-1 family of basic leucine zipper transcription factors comprises various combinations of Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra-1, and Fra-2) proteins, which upon dimer formation regulate gene transcription by binding to consensus response elements present in the promoter region of target genes (23).…”

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confidence: 99%

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ΔFosB Induces Osteosclerosis and Decreases Adipogenesis by Two Independent Cell-Autonomous Mechanisms

Kveiborg¹,

Sabatakos²,

Chiusaroli³

et al. 2004

Molecular and Cellular Biology

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Osteoblasts and adipocytes may develop from common bone marrow mesenchymal precursors. Transgenic mice overexpressing ⌬FosB, an AP-1 transcription factor, under the control of the neuron-specific enolase (NSE) promoter show both markedly increased bone formation and decreased adipogenesis. To determine whether the two phenotypes were linked, we targeted overexpression of ⌬FosB in mice to the osteoblast by using the osteocalcin (OG2) promoter. OG2-⌬FosB mice demonstrated increased osteoblast numbers and an osteosclerotic phenotype but normal adipocyte differentiation. This result firmly establishes that the skeletal phenotype is cell autonomous to the osteoblast lineage and independent of adipocyte formation. It also strongly suggests that the decreased fat phenotype of NSE-⌬FosB mice is independent of the changes in the osteoblast lineage. In vitro, overexpression of ⌬FosB in the preadipocytic 3T3-L1 cell line had little effect on adipocyte differentiation, whereas it prevented the induction of adipogenic transcription factors in the multipotential stromal cell line ST2. Also, ⌬FosB isoforms bound to and altered the DNA-binding capacity of C/EBP␤. Thus, the inhibitory effect of ⌬FosB on adipocyte differentiation appears to occur at early stages of stem cell commitment, affecting C/EBP␤ functions. It is concluded that the changes in osteoblast and adipocyte differentiation in ⌬FosB transgenic mice result from independent cell-autonomous mechanisms.Although osteoblasts and adipocytes represent two morphologically and functionally distinct cell types, it has been proposed that they may develop from a common mesenchymal precursor in the bone marrow (36,40,43). Indeed, an inverse relationship between adipocyte and osteoblast differentiation has been suggested, as exemplified by increased bone marrow adipocytes in age-related bone loss (4,6,29,32,60) or after treatment with glucocorticoids (57). Several regulatory factors involved in osteoblast and adipocyte differentiation have been identified (27,42,45). However, the identities of the factors that control commitment at the branching point between the osteoblast and adipocyte lineages and the degree of plasticity between the two cell types are still uncertain (33,38).We have recently reported that transgenic mice overexpressing ⌬FosB, a member of the activator protein 1 (AP-1) family of transcription factors, under the control of the neuron-specific enolase (NSE) promoter develop not only a severe and progressive osteosclerotic phenotype, characterized as increased bone formation, but also a pronounced decrease in adipogenesis and fat levels (25, 47, 53). The AP-1 family of basic leucine zipper transcription factors comprises various combinations of Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra-1, and Fra-2) proteins, which upon dimer formation regulate gene transcription by binding to consensus response elements present in the promoter region of target genes (23). Several studies have demonstrated an important regulatory role of AP-1 factors, especially the ...

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

ΔFosB Induces Osteosclerosis and Decreases Adipogenesis by Two Independent Cell-Autonomous Mechanisms

Kveiborg¹,

Sabatakos²,

Chiusaroli³

et al. 2004

Molecular and Cellular Biology

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“…GH receptor knockout mice; Sims et al 2000) and appearance of a bone phenotype has been reported in mice of old age (i.e. DfosB knockout mice; Sims et al 2002). Furthermore, it could be speculated that the emergence of a bone phenotype in the GPRC6A knockout mice requires a pathophysiological condition, such as a disease-induced state or a calcium depleted/overloaded state.…”

Section: Discussionmentioning

confidence: 99%

No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions

Wellendorph¹,

Johansen²,

Jensen³

et al. 2008

Journal of Molecular Endocrinology

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GPRC6A is a seven-transmembrane receptor mediating signaling by a wide range of L-a-amino acids, a signaling augmented by the divalent cations Ca 2C and Mg 2C . GPRC6A transcripts are detected in numerous mammalian tissues, but the physiological role of the receptor is thus far elusive. Analogously to the closely related calcium-sensing receptor, GPRC6A has been proposed to function as a metabolic sensor of Ca 2C and amino acids in bone and other tissues. In the present study, we have generated the first GPRC6A knockout mice and studied their phenotype with particular focus on bone homeostasis. The generated GPRC6A knockout mice are viable and fertile, develop normally, and exhibit no significant differences in body weight compared with wild-type littermates. Assessment of bone mineral density, histomorphometry, and bone metabolism demonstrated no significant differences between 13-week-old knockout and wild-type mice. In conclusion, our data do not support a role for GPRC6A in normal bone physiology.

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“…Dimerization with c-Fos appears unlikely, as we have previously shown that ␣NAC cannot potentiate the activity of the c-Fos/ c-Jun heterodimer (30). Potential c-Jun dimerization partners would include Fra-1 or ⌬FosB, which have been shown to play functional roles in osteoblasts in the regulation of bone mass accrual (21,23,39,40,43). We favor the possibility that the c-Jun homodimer regulates osteocalcin gene transcription and that this effect is maximized in the presence of the c-Jun coactivator, ␣NAC.…”

Section: Discussionmentioning

confidence: 99%

Sequence-Specific DNA Binding by the αNAC Coactivator Is Required for Potentiation of c-Jun-Dependent Transcription of the Osteocalcin Gene

Akhouayri

Quélo

St‐Arnaud

2005

Molecular and Cellular Biology

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Since the c-Jun coactivator ␣NAC was initially identified in a differential screen for genes expressed in differentiated osteoblasts, we examined whether the osteocalcin gene, a specific marker of terminal osteoblastic differentiation, could be a natural target for the coactivating function of ␣NAC. We had also previously shown that ␣NAC can specifically bind DNA in vitro, but it remained unclear whether the DNA-binding function of ␣NAC is expressed in vivo or if it is required for coactivation. We have identified an ␣NAC binding site within the murine osteocalcin gene proximal promoter region and demonstrated that recombinant ␣NAC or ␣NAC from ROS17/2.8 nuclear extracts can specifically bind this element. Using transient transfection assays, we have shown that ␣NAC specifically potentiated the c-Jun-dependent transcription of the osteocalcin promoter and that this activity specifically required the DNA-binding domain of ␣NAC. Chromatin immunoprecipitation confirmed that ␣NAC occupies its binding site on the osteocalcin promoter in living osteoblastic cells expressing osteocalcin. Inhibition of the expression of endogenous ␣NAC in osteoblastic cells by use of RNA interference provoked a decrease in osteocalcin gene transcription. Our results show that the osteocalcin gene is a target for the ␣NAC coactivating function, and we propose that ␣NAC is specifically targeted to the osteocalcin promoter through its DNA-binding activity as a means to achieve increased specificity in gene transcription.

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Regulating ΔFosB expression in adult tet-off-ΔFosB transgenic mice alters bone formation and bone mass

Cited by 24 publications

References 26 publications

ΔFosB Induces Osteosclerosis and Decreases Adipogenesis by Two Independent Cell-Autonomous Mechanisms

ΔFosB Induces Osteosclerosis and Decreases Adipogenesis by Two Independent Cell-Autonomous Mechanisms

No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions

Sequence-Specific DNA Binding by the αNAC Coactivator Is Required for Potentiation of c-Jun-Dependent Transcription of the Osteocalcin Gene

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