Cbfb Enhances the Osteogenic Differentiation of Both Human and Mouse Mesenchymal Stem Cells Induced by Cbfa-1 via Reducing Its Ubiquitination-Mediated Degradation

Lien, Chun‐Yang; Lee, Oscar K.; Su, Yeu

doi:10.1634/stemcells.2006-0391

Cited by 27 publications

(20 citation statements)

References 60 publications

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“…It has long been known that CBF␤ increases the Runx proteins' affinity for DNA, 88,89 and it was more recently shown that it protects them from ubiquitin-mediated proteolysis. 37,90 However, genetic data in both flies and worms hint at other functions. For example, overexpression of a Drosophila Runt protein that could bind DNA but not CBF␤ dominantly inhibited its wild-type counterpart, suggesting that it was occupying its DNA binding sites but forming nonfunctional complexes.…”

Section: Discussionmentioning

confidence: 99%

CBFβ is critical for AML1-ETO and TEL-AML1 activity

Roudaia

Cheney

Manuylova

et al. 2009

Blood

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Section: Discussionmentioning

confidence: 99%

CBFβ is critical for AML1-ETO and TEL-AML1 activity

Roudaia

Cheney

Manuylova

et al. 2009

Blood

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“…The WT Runx2 expression vector was described previously. (33) After being linearized by PmeI (New England Biolabs), the plasmids were transformed into BJ5183 cells, and successful recombination was verified by PacI (New England BioLabs) digestion. The vectors expressing His-tagged series of Runx2 were constructed as follows.…”

Section: Dna Constructionmentioning

confidence: 99%

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Huang¹,

Lin²,

Chao³

et al. 2012

Journal of Bone and Mineral Research

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Runx2 plays a crucial role in osteoblastic differentiation, which can be upregulated by bone morphogenetic proteins 2 (BMP2). Mitogenactivated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase (ERK) and p38, have been reported to be activated by BMP2 to increase Runx2 activity. The role of cjun-N-terminal kinase (JNK), the other kinase of MAPK, in osteoblastic differentiation has not been well elucidated. In this study, we first showed that JNK1 is activated by BMP2 in multipotent C2C12 and preosteoblastic MC3T3-E1 cell lines. We then showed that early and late osteoblastic differentiation, represented by ALP expression and mineralization, respectively, are significantly enhanced by JNK1 loss-of-function, such as treatment of JNK inhibitor, knockdown of JNK1 and ectopic expression of a dominant negative JNK1 (DN-JNK1). Consistently, BMP2-induced osteoblastic differentiation is reduced by JNK1 gain-offunction, such as enforced expression of a constitutively active JNK1 (CA-JNK1). Most importantly, we showed that Runx2 is required for JNK1-mediated inhibition of osteoblastic differentiation, and identified Ser104 of Runx2 is the site phosphorylated by JNK1 upon BMP2 stimulation. Finally, we found that overexpression of the mutant Runx2 (Ser104Ala) stimulates osteoblastic differentiation of C2C12 and MC3T3-E1 cells to the extent similar to that achieved by overexpression of wild-type (WT) Runx2 plus JNK inhibitor treatment. Taken together, these data indicate that JNK1 negatively regulates BMP2-induced osteoblastic differentiation through phosphorylation of Runx2 at Ser104. In addition, unraveling these mechanisms may help to develop new strategies in enhancing osteoblastic differentiation and bone formation. ß

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“…Control IgG or anti-Runx antibodies were included as indicated. (41,42), in part by limiting their ubiquitin-mediated degradation (43,44) and by increasing the affinity of Runx proteins for DNA (45). Therefore, to determine whether any member of the Runx family is required for the expression of RANKL, we silenced Cbfb using shRNAs introduced via lentiviral transduction.…”

Section: Figure 3 Runx2 Is Not Required For Rankl Expression In Mefsmentioning

confidence: 99%

Commitment to the Osteoblast Lineage Is Not Required for RANKL Gene Expression

Galli

Wang

et al. 2009

Journal of Biological Chemistry

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Differentiation of bone-resorbing osteoclasts from hematopoietic precursors depends upon expression of the cytokine receptor activator of NFB ligand (RANKL) by fibroblastic stromal cells, which some evidence suggests are of the osteoblast lineage. We have shown previously that hormonal-responsiveness of the murine RANKL gene is mediated in part by a distal enhancer that binds Runx2, a transcription factor required for commitment to the osteoblast lineage, supporting the idea that osteoclast-supporting stromal cells may be osteoblasts or their progenitors. However, in this study we demonstrate that parathyroid hormone (PTH) stimulation of RANKL in mice is not affected by a significant reduction in the number of osteoblasts. Consistent with this, neither Runx2, nor Cbfb, a binding partner essential for Runx activity, are required for basal or PTH-stimulated RANKL expression in fibroblastic stromal cell models. Nonetheless, RANKL responsiveness to PTH was elevated in cultured calvaria cells expressing high levels of osterix, another transcription factor required for osteoblast differentiation, and this was associated with elevated PTH receptor expression. The responsiveness of RANKL to 1,25-dihydroxyvitamin D 3 was not elevated in the osterix-expressing cells. Together, these results suggest that commitment to the osteoblast lineage is not a requirement for RANKL gene transcription in fibroblastic stromal cells but may enhance responsiveness of this gene to specific hormones via control of their receptors.In the adult skeleton, bone is constantly renewed via the coordinated activity of osteoclasts that resorb bone and osteoblasts that form bone. These cells function within an anatomically distinct structure known as the basic multicellular unit (BMU), in which the osteoclasts are located in the lead and are followed by osteoblasts (1). Because of this organization, bone formation occurs only at sites of prior bone resorption and the recruitment of osteoblasts to such sites is known as coupling. While the mechanisms that underlie coupling are unknown, two different explanations have been proposed. According to the first, release of factors, such as TGF␤, from the bone matrix as a consequence of osteoclast activity recruits osteoblast progenitors and promotes their differentiation (2). Thus, osteoblastogenesis in this "serial" pathway of coupling is a consequence of osteoclastogenesis (3). However, in view of the fact that osteoclastogenesis depends upon support from stromal cells that may be of the osteoblastic lineage, the existence of a parallel pathway has been proposed (4). According to the parallel pathway model, osteoclast and osteoblast differentiation occur simultaneously due in part to the requirement of osteoblast lineage cells for osteoclast differentiation.The idea that osteoblast lineage cells are required for osteoclast differentiation originated from studies showing that osteoblasts or osteoblast-like cells, not osteoclast precursors, are targets of hormones that stimulate bone resorption (5-7). It ha...

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Cbfb Enhances the Osteogenic Differentiation of Both Human and Mouse Mesenchymal Stem Cells Induced by Cbfa-1 via Reducing Its Ubiquitination-Mediated Degradation

Cited by 27 publications

References 60 publications

CBFβ is critical for AML1-ETO and TEL-AML1 activity

CBFβ is critical for AML1-ETO and TEL-AML1 activity

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Commitment to the Osteoblast Lineage Is Not Required for RANKL Gene Expression

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