FOXO1 modulates osteoblast differentiation

Siqueira, Michelle F.; Flowers, Stephen; Bhattacharya, Rupa; Faibish, Dan; Behl, Yugal; Kotton, Darrell N.; Gerstenfeld, Lou; Morán, Elizabeth; Graves, Dana T.

doi:10.1016/j.bone.2011.01.019

Cited by 73 publications

(83 citation statements)

References 30 publications

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“…The FOXO protein family, one of several known downstream targets of activated AKT, has been associated with expression of Runx2 in osteoblasts, human embryonic stem cells and prostate cancer cells, although data from these studies are not compelling 31–34 . We found that FOXO1 and FOXO3a are highly expressed in VSMC compared with FOXO4 (Online Supplemental Fig II).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have suggested a potential link between FOXO and Runx2 expression in other cell types 31–34 . In osteoblasts and human embryonic stem cells, FOXO1 or FOXO3 increases Runx2 expression; whereas other studies suggest that FOXO1 inhibits Runx2 activity in osteoblasts or prostate cancer cells 31–34 . Therefore, the function of FOXOs in regulating Runx2 expression may be cell type-dependent.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of FOXO1/3 Promotes Vascular Calcification

Deng

Huang

Sun

et al. 2015

ATVB

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Objective Vascular calcification is a characteristic feature of atherosclerosis, diabetes and end-stage renal disease. We have demonstrated that activation of AKT upregulates Runx2, a key osteogenic transcription factor that is crucial for calcification of vascular smooth muscle cells (VSMC). Using mice with SMC-specific deletion of PTEN, a major negative regulator of AKT, the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO-mediated Runx2 upregulation and VSMC calcification. Approaches and Results SMC-specific PTEN deletion mice were generated by crossing PTEN floxed mice with SM22α-Cre transgenic mice. The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo. Runx2 knockdown did not affect proliferation but blocked calcification of the PTEN deficient VSMC, suggesting that PTEN deletion promotes Runx2-depedent VSMC calcification that is independent of proliferation. At the molecular level, PTEN deficiency increased the amount of Runx2 post-transcriptionally by inhibiting Runx2 ubiquitination. AKT activation increased phosphorylation of FOXO1/3 that led to nuclear exclusion of FOXO1/3. FOXO1/3 knockdown in VSMC phenocopied the PTEN deficiency, demonstrating a novel function of FOXO1/3, as a downstream signaling of PTEN/AKT, in regulating Runx2 ubiquitination and VSMC calcification. Using heterozygous SMC-specific PTEN deficient mice and atherogenic ApoE−/− mice, we further demonstrated AKT activation, FOXO phosphorylation and Runx2 ubiquitination in vascular calcification in vivo. Conclusions Our studies have determined a new causative effect of SMC-specific PTEN deficiency on vascular calcification, and demonstrated that FOXO1/3 plays a crucial role in PTEN/AKT-modulated Runx2 ubiquitination and VSMC calcification.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of FOXO1/3 Promotes Vascular Calcification

Deng

Huang

Sun

et al. 2015

ATVB

View full text Add to dashboard Cite

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“…P Ͻ .01 compared with control siRNA. doi: 10.1210/me.2013-1152 mend.endojournals.org cells (43,44). It has been shown that Foxo1 can interact directly with Runx2, although the exact impact of Foxo1 on Runx2 functional activity is controversial (27)(28)(29).…”

Section: Discussionmentioning

confidence: 97%

Knockdown of PRKAR1A, the Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells

Zhang

Manchanda

et al. 2014

Molecular Endocrinology

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PRKAR1A is the gene encoding the type 1A regulatory subunit of protein kinase A, and it is the cause of the inherited human tumor syndrome Carney complex. Data from our laboratory has demonstrated that Prkar1a loss causes tumors in multiple cell lineages, including neural crest cells and osteoblasts. We have proposed that one mechanism by which tumorigenesis occurs is through the failure of terminal differentiation. In the present study, we directly test the effects of Prkar1a reduction on osteogenic differentiation in mouse and human cells in vitro. We found that Prkar1a levels noticeably increased during osteoblastic differentiation, indicating a positive correlation between the expression of Prkar1a and osteogenic potential. To validate this hypothesis, we generated stable Prkar1a knockdown in both mouse and human cells. These cells displayed significantly suppressed bone nodule formation and decreased expression of osteoblast markers such as osteocalcin and osteopontin. These observations imply that the antiosteogenic effect of Prkar1a ablation is not species or cell line specific. Furthermore, because Runt-related transcription factor-2 (Runx2) is a key mediator of osteoblast differentiation, we reasoned that the function of this transcription factor may be inhibited by Prkar1a knockdown. Chromatin immunoprecipitation and luciferase assays demonstrated that Prkar1a ablation repressed DNA binding and function of Runx2 at its target genes. Additionally, we determined that this effect is likely due to reductions in the Runx2-cooperating transcription factors forkhead box O1 and activating transcription factor 4. Taken together, this study provides direct evidence that ablation of Prkar1a interferes with signaling pathways necessary for osteoblast differentiation.

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“…As shown in Supplementary Fig. S1, different genes involved in osteogenic differentiation are upregulated in ATP-treated BM-hMSCs compared to the untreated sample, such as osteoblastic transcription factors (ie, RUNX2 [38] and FOXO1 [39]), osteoblastic markers (ie, ANKH, BGLAP, and SPP1 [40,41]), and osteogenic growth factors (ie, BMP2, BMP6, WISP2, and IGFBP5 [42][43][44][45]). Moreover, ATP treatment of BM-hMSCs increased the expression of adipogenic transcription factors (ie, CEBPA, PPARGC1A, and CEBPB) [46] and adipocytespecific proteins (ie, ADFP, PC, and SPG20 [47][48][49]) (Supplementary Fig.…”

Section: Gene Expression Profile Of Atp-treated Undifferentiated Bm-hmentioning

confidence: 99%

Extracellular Purines Promote the Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells to the Osteogenic and Adipogenic Lineages

Ciciarello

Zini

Rossi

et al. 2013

Stem Cells and Development

101

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Extracellular nucleotides are potent signaling molecules mediating cell-specific biological functions, mostly within the processes of tissue damage and repair and flogosis. We previously demonstrated that adenosine 5¢-triphosphate (ATP) inhibits the proliferation of human bone marrow-derived mesenchymal stem cells (BMhMSCs), while stimulating, in vitro and in vivo, their migration. Here, we investigated the effects of ATP on BM-hMSC differentiation capacity. Molecular analysis showed that ATP treatment modulated the expression of several genes governing adipogenic and osteoblastic (ie, WNT-pathway-related genes) differentiation of MSCs. Functional studies demonstrated that ATP, under specific culture conditions, stimulated adipogenesis by significantly increasing the lipid accumulation and the expression levels of the adipogenic master gene PPARc (peroxisome proliferator-activated receptor-gamma). In addition, ATP stimulated osteogenic differentiation by promoting mineralization and expression of the osteoblast-related gene RUNX2 (runt-related transcription factor 2). Furthermore, we demonstrated that ATP stimulated adipogenesis via its triphosphate form, while osteogenic differentiation was induced by the nucleoside adenosine, resulting from ATP degradation induced by CD39 and CD73 ectonucleotidases expressed on the MSC membrane. The pharmacological profile of P2 purinergic receptors (P2Rs) suggests that adipogenic differentiation is mainly mediated by the engagement of P2Y1 and P2Y4 receptors, while stimulation of the P1R adenosine-specific subtype A2B is involved in adenosine-induced osteogenic differentiation. Thus, we provide new insights into molecular regulation of MSC differentiation.

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FOXO1 modulates osteoblast differentiation

Cited by 73 publications

References 30 publications

Inhibition of FOXO1/3 Promotes Vascular Calcification

Inhibition of FOXO1/3 Promotes Vascular Calcification

Knockdown of PRKAR1A, the Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells

Extracellular Purines Promote the Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells to the Osteogenic and Adipogenic Lineages

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