Runx2 Regulates G Protein-coupled Signaling Pathways to Control Growth of Osteoblast Progenitors

Teplyuk, Nadiya M.; Galindo, Mario; Teplyuk, Viktor I.; Pratap, Jitesh; Young, Daniel W.; Lapointe, David S.; Javed, Amjad; Stein, Janet L.; Lian, Jane B.; Wijnen, André J. van

doi:10.1074/jbc.m802453200

Cited by 118 publications

(124 citation statements)

References 73 publications

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“…Runx2 is known as an important regulator of cell proliferation, and its ablation increases the growth of cultured cells (15,(19)(20)(21). On the other hand, forced expression of Runx2 suppresses proliferation of osteoblasts (15,22) and non-osteogenic cells (23). Hence, Runx2 has been proposed as a gene related to cancer (24).…”

Section: Discussionmentioning

confidence: 99%

Combination of Runx2 and BMP2 increases conversion of human ligamentum flavum cells into osteoblastic cells

hyunnam

Min²,

Jeong³

et al. 2011

BMB Reports

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Section: Discussionmentioning

confidence: 99%

Combination of Runx2 and BMP2 increases conversion of human ligamentum flavum cells into osteoblastic cells

hyunnam

Min²,

Jeong³

et al. 2011

BMB Reports

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“…(17,18) Runx2 controls lineage commitment, proliferation, and anabolic functions of osteoblasts as the subnuclear effector of multiple signaling axes. (19) Runx2 is tightly regulated during the cell cycle at both the transcriptional and posttranslational levels. (20) Phosphorylation of Runx2 during the cell cycle by distinct cyclin/CDK complexes regulates its activity or stability by a proteasome-dependent mechanism.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

Ann

Kim

Choi

et al. 2010

Journal of Bone and Mineral Research

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Notch1 genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch1 signaling in osteogenesis is not well defined. Notch1 controls osteoblast differentiation by affecting Runx2, but the question arises whether normal osteoblastic differentiation can occur regardless of the presence of Notch1. In this study, we observed the downregulation of Notch1 signaling during osteoblastic differentiation. BMPR‐IB/Alk6‐induced Runx2 proteins reduced Notch1 activity to a marked degree. Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1‐IC‐RBP‐Jk complex. Using deletion mutants, we also determined that the N‐terminal domain of Runx2 was crucial to the binding and inhibition of the N‐terminus of the Notch1 intracellular domain. Notably, upregulation of the Runx2 protein level paralleled reduced expression of Hes1, which is a downstream target of Notch1, during osteoblast differentiation. Collectively, our data suggest that Runx2 is an inhibitor of the Notch1 signaling pathway during normal osteoblast differentiation. © 2011 American Society for Bone and Mineral Research.

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“…Moreover, Teplyuk and colleagues showed that Runx2 controls enzymes (e.g., Cyp11a1) that support the production of pregnenolone (46) as well as the expression of the nongenomic receptor for estrogen (Gpr30/Gper), which is necessary for osteoblast proliferation in cell culture (47). Our study shows that Runx2 increases the expression of aromatase, the key enzyme for the conversion of androgen to estrogen.…”

Section: Discussionmentioning

confidence: 59%

“…Furthermore, Runx2 was recently shown to control the expression of GPR30/GPER, which represents a nongenomic cell surface receptor for estrogen that is essential for osteoblast proliferation in cell culture (47). Although accumulating evidence implicates a functional association of Runx2 with estrogen signaling (13,21,45,48), Runx2 has not been directly shown to control estrogen biosynthesis.…”

mentioning

confidence: 99%

The Gene for Aromatase, a Rate-Limiting Enzyme for Local Estrogen Biosynthesis, Is a Downstream Target Gene of Runx2 in Skeletal Tissues

Jeong

Jung

Kim

et al. 2010

Molecular and Cellular Biology

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The essential osteoblast-related transcription factor Runx2 and the female steroid hormone estrogen are known to play pivotal roles in bone homeostasis; however, the functional interaction between Runx2-and estrogenmediated signaling in skeletal tissues is minimally understood. Here we provide evidence that aromatase (CYP19), a rate-limiting enzyme responsible for estrogen biosynthesis in mammals, is transcriptionally regulated by Runx2. Consistent with the presence of multiple Runx2 binding sites, the binding of Runx2 to the aromatase promoter was demonstrated in vitro and confirmed in vivo by chromatin immunoprecipitation assays. The bone-specific aromatase promoter is activated by Runx2, and endogenous aromatase gene expression is upregulated by Runx2 overexpression, establishing the aromatase gene as a target of Runx2. The biological significance of the Runx2 transcriptional control of the aromatase gene is reflected by the enhanced estrogen biosynthesis in response to Runx2 in cultured cells. Reduced in vivo expression of skeletal aromatase gene and low bone mineral density are evident in Runx2 mutant mice. Collectively, these findings uncover a novel link between Runx2-mediated osteoblastogenic processes and the osteoblast-mediated biosynthesis of estrogen as an osteoprotective steroid hormone.

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Runx2 Regulates G Protein-coupled Signaling Pathways to Control Growth of Osteoblast Progenitors

Cited by 118 publications

References 73 publications

Combination of Runx2 and BMP2 increases conversion of human ligamentum flavum cells into osteoblastic cells

Combination of Runx2 and BMP2 increases conversion of human ligamentum flavum cells into osteoblastic cells

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

The Gene for Aromatase, a Rate-Limiting Enzyme for Local Estrogen Biosynthesis, Is a Downstream Target Gene of Runx2 in Skeletal Tissues

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