Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis

Sabatakos, G.; Sims, Natalie A.; Chen, J; Aoki, Kazuhiro; Kelz, Max B.; Amling, Michael; Bouali, Yasmina; Mukhopadhyay, Kanya; Ford, K. E.; Nestler, Eric J.; Baron, Roland

doi:10.1038/79683

Cited by 321 publications

(264 citation statements)

References 33 publications

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“…In most murine models of increased bone production attributable to osteoblast-intrinsic manipulations, a compensatory increase in osteoclastic activity is typically seen (12,13). However, this is not always the case (14)(15)(16). Although the mechanisms controlling mesenchymal/osteoclast cross-talk are incompletely understood, expression of the crucial osteoclastogenic factors TNFSF11 [receptor activator of nuclear factor-κB ligand (RANKL)] and TNFRSF11B [osteoprotegerin (OPG)] by chondrocytes, osteoblasts, stromal cells, and osteocytes plays a dominant role (17)(18)(19).…”

mentioning

confidence: 98%

Control of bone resorption in mice by Schnurri-3

Wein

Jones

Shim

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mice lacking the large zinc finger protein Schnurri-3 (Shn3) display increased bone mass, in part, attributable to augmented osteoblastic bone formation. Here, we show that in addition to regulating bone formation, Shn3 indirectly controls bone resorption by osteoclasts in vivo. Although Shn3 plays no cell-intrinsic role in osteoclasts, Shn3-deficient animals show decreased serum markers of bone turnover. Mesenchymal cells lacking Shn3 are defective in promoting osteoclastogenesis in response to selective stimuli, likely attributable to reduced expression of the key osteoclastogenic factor receptor activator of nuclear factor-κB ligand. The bone phenotype of Shn3-deficient mice becomes more pronounced with age, and mice lacking Shn3 are completely resistant to disuse osteopenia, a process that requires functional osteoclasts. Finally, selective deletion of Shn3 in the mesenchymal lineage recapitulates the high bone mass phenotype of global Shn3 KO mice, including reduced osteoclastic bone catabolism in vivo, indicating that Shn3 expression in mesenchymal cells directly controls osteoblastic bone formation and indirectly regulates osteoclastic bone resorption.cAMP response element binding protein | receptor activator of nuclear factor-κB ligand | secondary hyperparathyroidism S chnurri-3 (Shn3) is a large zinc finger protein belonging to the small group of zinc finger, acid-rich, and serine-threonine rich (ZAS) family proteins (1). Previous in vitro studies have implicated a role for Shn3 in diverse processes, such as Ig gene rearrangement, cell survival, TNF signaling in macrophages, and IL-2 gene expression in helper T lymphocytes (2-6). We recently discovered that mice with germline deletion of Shn3 displayed a massive increase in bone mass, revealing an unexpected role for this protein in the skeletal system (5). Shn3-deficient animals showed markedly augmented osteoblastic bone formation in vivo. Consistently, cultured primary osteoblasts lacking Shn3 express increased levels of classic osteoanabolic genes and produce increased amounts of mineralized ECM. In osteoblasts, Shn3 functions, at least in part, by regulating Runx2 protein levels via its ubiquitination.A central dogma in skeletal biology is that bone formation and resorption are coupled, such that manipulations that increase bone production by osteoblasts typically increase bone catabolism by osteoclasts (7-9). Pharmacological augmentation of bone production in humans with recombinant parathyroid hormone (PTH) leads to a compensatory increase in serum markers of bone turnover. Likewise, inhibition of bone resorption following bisphosphonate or denosumab treatment leads to decreased bone production (10, 11). In most murine models of increased bone production attributable to osteoblast-intrinsic manipulations, a compensatory increase in osteoclastic activity is typically seen (12, 13). However, this is not always the case (14-16). Although the mechanisms controlling mesenchymal/osteoclast cross-talk are incompletely understood, expression of the cruci...

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mentioning

confidence: 98%

Control of bone resorption in mice by Schnurri-3

Wein

Jones

Shim

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…MicroCT scans, quantitative computerized tomography and histomorphometry of mouse tibia were performed as described (21,22) (for details see Supporting Text).…”

Section: Lithium and Parathyroid Hormone (Pth) Treatment Regimens Andmentioning

confidence: 99%

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Clément-Lacroix

Morvan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

453

327

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One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3␤ and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains (Lrp5 ؊/؊ , SAMP6, and C57BL͞6) and assessed the effect on bone metabolism after 4 weeks of therapy. Lrp5 ؊/؊ mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL͞6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from Lrp5 ؊/؊ mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Wnt pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans.anabolic ͉ osteoporosis ͉ therapy

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“…[9][10][11][12] The fosB gene products, especially DFosB, have been reported to regulate potentially the neuronal function as well as such cell fates as cell proliferation and differentiation. 7,[13][14][15] We previously reported that the expression of FosB and DFosB increased in the rat hippocampal CA1 neurons prior to their delayed death after ischemic reperfusion, 16 thus suggesting that FosB or DFosB may be involved in the regulation of such programmed cell death in addition to regulation of cell proliferation and differentiation. It has been well documented that c-Fos and c-Jun play important roles in the induction of apoptosis; 4 however, there is little literature reporting on the fact that FosB or DFosB regulate the induction of programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Among four members of fos family genes (c-fos, fosB, fra-1, fra-2), only the fosB gene forms two mature mRNAs, fosB and DfosB, by alternative splicing, 5 each of which encodes more than two polypeptides by the alternative initiation of translation. 6,7 The DFosB protein encoded by DfosB mRNA lacks the C-terminal 101 amino-acid region of FosB protein encoded by fosB mRNA, which contains several functional motifs responsible for interaction with other transcription factors. 5,8 The fosB gene products form heterodimers with c-Jun, JunB or JunD proteins in the same manner as c-Fos protein, thereby stimulating the DNA binding activities.…”

Section: Introductionmentioning

confidence: 99%

ΔFosB, but not FosB, induces delayed apoptosis independent of cell proliferation in the Rat1a embryo cell line

et al. 2003

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The fates of Rat1a cells expressing FosB and DFosB as fusion proteins (ER-FosB, ER-DFosB) with the ligand binding domain of human estrogen receptor were examined. The binding of estrogen to the fusion proteins resulted in their nuclear translocation and triggered cell proliferation, and thereafter delayed cell death was observed only in cells expressing ER-DFosB. The proliferation of Rat1a cells, but not cell death triggered by ER-DFosB, was completely abolished by butyrolactone I, an inhibitor of cyclinedependent kinases, and was partly suppressed by antisense oligonucleotides against galectin-1, whose expression is induced after estrogen administration. The cell death was accompanied by the activation of caspase-3 and -9, the fragmentation of the nuclear genome and cytochrome c release from the mitochondria, and was suppressed by zDEVD-fmk and zLEHD-fmk but not zIETD-fmk. The cell death was not suppressed by exogenous His-PTD-Bcl-x L at all, suggesting involvement of a Bcl-x L -resistant pathway for cytochrome c release.

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Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis

Cited by 321 publications

References 33 publications

Control of bone resorption in mice by Schnurri-3

Control of bone resorption in mice by Schnurri-3

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

ΔFosB, but not FosB, induces delayed apoptosis independent of cell proliferation in the Rat1a embryo cell line

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