Two of four alternatively spliced isoforms of RUNX2 control osteocalcin gene expression in human osteoblast cells

Makita, Naoyuki; Suzuki, Motoo; Asami, Shiori; Takahata, Rintaroh; Kohzaki, Daika; Kobayashi, Shinya; Hakamazuka, Takashi; Hozumi, Nobumichi

doi:10.1016/j.gene.2007.12.025

Cited by 52 publications

(72 citation statements)

References 57 publications

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“…Runx2 positively and negatively regulates the osteoblast-specific genes by binding to its target promoters (15, 30 -32). For example, bone-specific expression of OC is regulated principally by Runx2 (25). BMP also induces the expression of the negative regulator such as Tob (33).…”

Section: Discussionmentioning

confidence: 99%

“…The right panels of A and B depict the eluted AR-S concentrations, indicating the level of mineralization. Moreover, many osteoblast-specific marker genes such as OC and BSP are reported to be regulated by Runx2 (22,25). Therefore, we examined the effect of ERR␥ on the transcriptional activity of Runx2 on osteoblast-specific genes.…”

Section: Figure 4 Err␥ Decreases Bmp2-induced Mineralized Nodule Formentioning

confidence: 99%

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The Orphan Nuclear Receptor Estrogen Receptor-related Receptor γ Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation

Jeong

Lee

Park

et al. 2009

Journal of Biological Chemistry

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Estrogen receptor-related receptor ␥ (ERR␥/ERR3/NR3B3) is a member of the orphan nuclear receptor with important functions in development and homeostasis. Recently it has been reported that ERR␣ is involved in osteoblast differentiation and bone formation. In the present study we examined the role of ERR␥ in osteoblast differentiation. Here, we showed that ERR␥ is expressed in osteoblast progenitors and primary osteoblasts, and its expression is increased temporarily by BMP2. Overexpression of ERR␥ reduced BMP2-induced alkaline phosphatase activity and osteocalcin production as well as calcified nodule formation, whereas inhibition of ERR␥ expression significantly enhanced BMP2-induced osteogenic differentiation and mineralization, suggesting that endogenous ERR␥ plays an important role in osteoblast differentiation. In addition, ERR␥ significantly repressed Runx2 transactivity on osteocalcin and bone sialoprotein promoters. We also observed that ERR␥ physically interacts with Runx2 in vitro and in vivo and competes with p300 to repress Runx2 transactivity. Notably, intramuscular injection of ERR␥ strongly inhibited BMP2-induced ectopic bone formation in a dose-dependent manner. Taken together, these results suggest that ERR␥ is a novel negative regulator of osteoblast differentiation and bone formation via its regulation of Runx2 transactivity.Bone formation is a series of well orchestrated lineage-specific differentiation events (1). Osteoblasts, which play key roles in bone formation, are derived from pluripotent mesenchymal stem cells that have the capacity to differentiate into myocytes, adipocytes, and chondrocytes (2). Osteoblasts possess the necessary components to form bone matrix, which allows subsequent mineralization. Several hormones, growth factors, cytokines, and nuclear receptor proteins regulate these sequential events to trigger a complex network of signaling pathways.Bone morphogenetic proteins (BMPs) 5 are members of the transforming growth factor ␤ family and were originally identified by their capacity to induce ectopic bone formation (3, 4). Among the BMP family members, the action of BMP2 has been studied extensively in embryonic skeletal development, postnatal bone remodeling, and bone repair (5, 6). BMP2 promotes the commitment of pluripotent mesenchymal cells to the osteoblast lineage by regulating the signals that stimulate the specific transcriptional programs required for bone formation (5, 7).A master regulator of osteoblasts, Runx2, is indispensable for a skeletal development and maturation. Targeted disruption of Runx2 results in a complete lack of functional osteoblasts (8, 9). Runx2 directly regulates osteoblast-specific genes such as osteocalcin (OC), bone sialoprotein (BSP), osteopontin, and type I collagen through binding to specific DNA enhancer elements of its target gene promoters (4). In addition, Runx2 interacts with a variety of transcription factors (10) and recruits both co-activators (11-13) and co-repressors (14, 15) to form a complex on its target promoter. Theref...

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Section: Discussionmentioning

confidence: 99%

Section: Figure 4 Err␥ Decreases Bmp2-induced Mineralized Nodule Formentioning

confidence: 99%

The Orphan Nuclear Receptor Estrogen Receptor-related Receptor γ Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation

Jeong

Lee

Park

et al. 2009

Journal of Biological Chemistry

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“…Its deficiency in homozygots leads to different types of bone dysplasia, consisting of genetically determined disorders in the structure of the skeleton (Marie, 2008). Runx2 is also involved in processes related to the maturation of cartilage cells (Makita et al, 2008). However, during dentinogenesis, Runx2 expression is downregulated, and Runx2 inhibits the terminal differentiation of odontoblast.…”

Section: Runx2 (Runt-related Transcription Factor 2)mentioning

confidence: 99%

Transcriptional Control of Osteogenesis

Witkowska-Zimny¹

2012

Osteogenesis

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“…This hypothesis was confirmed since they could not transactivate the two promoters nor were they able to interact with the intact runx2 or its canonical binding sites. The role of human alternative RUNX2 isoforms was examined (Makita et al, 2008) and it was suggested that RUNX2 could have a novel function during osteoblast differentiation, regulating expression of target genes through alternatively spliced forms and posttranslational modifications. The generation of full-length and truncated protein isoforms derived from a given gene has been suggested to be a way of mediating, under specific physiological or pathological conditions, localized functional antagonism (Bae et al, 1994;Zhang et al, 1997;Akiyama et al, 1999).…”

Section: Xlrunx2 Isoforms and Regulation Of Target Gene Transcriptionmentioning

confidence: 99%

Dual transcriptional regulation by runx2 of matrix Gla protein in Xenopus laevis

Fazenda

Simões

Kelsh

et al. 2010

Gene

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Two of four alternatively spliced isoforms of RUNX2 control osteocalcin gene expression in human osteoblast cells

Cited by 52 publications

References 57 publications

The Orphan Nuclear Receptor Estrogen Receptor-related Receptor γ Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation

The Orphan Nuclear Receptor Estrogen Receptor-related Receptor γ Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation

Transcriptional Control of Osteogenesis

Dual transcriptional regulation by runx2 of matrix Gla protein in Xenopus laevis

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