Gene profile analysis of osteoblast genes differentially regulated by histone deacetylase inhibitors

Schroeder, Tania M.; Nair, Aswathy K; Staggs, Rodney; Lamblin, Anne Françoise; Westendorf, Jennifer J.

doi:10.1186/1471-2164-8-362

Cited by 62 publications

(55 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Five highly up-regulated genes (Mknk2, ϩ5.84-fold; Slc9a3r1, ϩ4.59-fold; Ptpn1, ϩ2.71-fold; Socs3, ϩ2.19-fold; and Pik3cb, ϩ2.16-fold) play a critical role in insulin signaling. Slc9a3r1 stood out among these because we previously found it to be one of the most highly and consistently induced genes in MC3T3 cells treated with other HDIs (20). Increases in Slc9a3r1/Nherf1 expression in response to SAHA were confirmed by qPCR (Fig.…”

Section: Saha Enhances Osteoblast Differentiation and Induces Histonementioning

confidence: 73%

See 1 more Smart Citation

Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation

Dudakovic¹,

Evans²,

Li³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Histone deacetylase (HDAC) inhibition promotes bone formation in vitro via undefined epigenetic events. Results: Microarray and ChIP-Seq analyses revealed genomic areas where H4 acetylation is altered by HDAC inhibitors and identified differentially regulated genes. Conclusion: Suberoylanilide hydroxamic acid increases H4 acetylation and suppresses phosphorylation of insulin/Akt signaling mediators in osteoblasts. Significance: Epigenetic profiling is a powerful means to gain mechanistic insights into bone anabolic processes.

show abstract

Section: Saha Enhances Osteoblast Differentiation and Induces Histonementioning

confidence: 73%

“…We previously reported that HDIs promote osteoblast differentiation of MC3T3-E1 osteoblasts, primary osteoblasts, and ex vivo calvarial cultures (12) and differentially regulate expression of numerous genes in osteoblasts (20). In this study, we investigated the epigenetic events that promote osteoblast differentiation in vitro after exposure to the HDI SAHA.…”

mentioning

confidence: 99%

Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation

Dudakovic¹,

Evans²,

Li³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…We previously showed that multiple HDACi drugs, including SAHA, significantly increase expression of the Nherf1 scaffold protein in osteoblasts (15,16,18). HDACi treatment of differentiating MC3T3 cells in our co-culture system similarly increased expression of both Nherf1 mRNA and protein (Fig.…”

Section: Osteoblasts Protect Aml Isolates From Apoptosis In a Co-cultmentioning

confidence: 99%

“…HDACi are known to directly target cancer cells by increasing expression of many proteins including those that regulate tumor suppression, DNA repair, and cell-cycle arrest. Because HDACi have also been shown to alter expression of many genes within cells of the osteoblast lineage (15)(16)(17)(18), we hypothesized that HDACi might also target the leukemic microenvironment. HDACi have been previously shown to up-regulate Nherf1 (also known as EBP-50), a scaffold protein mutated in human hypophosphatemic nephrolithiasis/osteoporosis type 2.…”

mentioning

confidence: 99%

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Kremer

Dudakovic

Hess

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently upregulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1␣ (PP1␣) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1␣ or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1␣-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis.For decades, research into drug treatments for acute myeloid leukemia (AML) 2 has focused on directly targeting AML cells for destruction. Even though complete remission rates have improved, relapse remains a problem in the majority of patients with this disease. The bone marrow microenvironment has gained attention as a protective environment that promotes survival of AML stem cells, despite the killing of the majority of AML cells by standard chemotherapeutics (1-5). The endosteum, the tissue between the bone marrow and ossified surface, has been particularly implicated as a protective niche because AML stem cells are localized to this region following chemotherapeutics (6, 7). Within the endosteal niche, cells of the osteoblast (bone-generating) lineage have been identified as critical mediators of AML cell survival in the bone marrow (4, 8). Transgenic mice expressing activated ␤-catenin specifically in osteoblasts develop myeloid malignancy, consistent with the idea that osteoblasts promote this disease (9). Unfortunately, the molecular mechanisms responsible for osteoblast-mediated protection of AML cells are incompletely understood. This lack of knowledge prevents effective therapeutic manipulation of the bone marrow microenvironment as a way to enhance targeting of AML cells within the bone marrow. We...

show abstract

“…Ранние изменения в экспрессии генов затрагивают также 2 рецепторных гена Wnt-пути -ФРЗ 1 и 4. Отмечено, что экспрессия RANKL усиливается при ацетилировании ги-стонов H3 и H4 в промоторе RANKL [11,12]. HDAC 1, 3, 4, 5 являются важными факторами в регуляции остеобластогенеза.…”

Section: актуальные вопросы эндокринологииunclassified

Epigenetic Aspects of Osteoporosis

Belaya

Rozhinskaya

et al. 2015

Annals RAMS

View full text Add to dashboard Cite

Epigenetic Aspects of Osteoporosis This review describes the epigenetic regulation of osteoblastogenesis and osteoclastogenesis and its future implementation in the diagnosis and treatment of osteoporosis. A considerable part of the review is dedicated to the microRNAs (miRNAs). miRNAs are small regulatory factors that regulate gene expression, by post-transcriptional regulation of genes playing an important role in numerous cellular ВведениеОстеопороз -это системное заболевание скелета, характеризующееся снижением костной массы, наруше-нием микроархитектоники костной ткани и, как след-ствие, повышением хрупкости скелета и переломами при минимальной травме, в частности при падении с высоты собственного роста, неловком движении, кашле, чиха-нии, объятиях и вообще без видимого травматического вмешательства [1]. Так, переломы тел позвонков в ряде случаев длительное время остаются недиагностированны-ми именно из-за отсутствия даже минимальной травмы при их возникновении.Значительная распространенность остеопороза и тяжелые последствия низкотравматичных перело-мов -повышение летальности, стойкая инвалидизация пациентов, необходимость в постороннем уходе -при-влекают пристальное внимание к данной проблеме во всем мире [2]. Согласно данным Международного фонда остеопороза, более 200 млн человек в мире страдают от остеопороза. В России число больных остеопорозом со-ставляет порядка 14 млн человек [3]. Тенденция к увели-чению продолжительности жизни населения приводит к увеличению заболеваемости остеопорозом у женщин в постменопаузе и мужчин старшей возрастной категории. Таким образом, наряду с развитием вторичного осте-опороза, по мнению практикующих эндокринологов, ревматологов, гастроэнтерологов, неврологов и многих других узких специалистов, каждой 3-й женщине и каждому 5-му мужчине старше 50 лет угрожает низко-травматичный перелом в течение оставшегося периода жизни. Вместе с тем существующие методы ранней диагностики остеопороза, такие как двухэнергетическая рентгеновская остеоденситометрия, оставляют недиа-гностированными до 50% пациентов [1]. С другой сторо-ны, эффективность современных препаратов для лече-ния остеопороза и предупреждения низкотравматичных переломов позволяет уменьшить риск переломов раз-личной локализации примерно на 50% c максимальным эффектом для предупреждения переломов тел позвонков (до 70%), но худшими результатами в отношении вне-позвоночных переломов (до 25%) [4,5]. Именно поэтому необходимы дальнейшие исследования с целью поиска новых диагностических тестов и новых методов лечения этого социально значимого заболевания. Основы регуляции костного ремоделирования и эпигенетикиВ большинстве случаев остеопороз развивается вслед-ствие нарушений костного ремоделирования: взаимодей-ствия костеобразующих (остеобластов) и разрушающих (остеокластов) костную ткань клеток. Костное ремоде-лирование позволяет поддерживать прочность и адаптив-ность скелета человека в течение всей жизни, однако в постменопаузе у женщин и в старшей возрастной группе у мужчин имеется тенденция к отрицательному балансу с

show abstract

Gene profile analysis of osteoblast genes differentially regulated by histone deacetylase inhibitors

Cited by 62 publications

References 40 publications

Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation

Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Epigenetic Aspects of Osteoporosis

Contact Info

Product

Resources

About