BMP2 Regulates Osterix through Msx2 and Runx2 during Osteoblast Differentiation

Matsubara, Takuma; Kida, Kumiko; Yamaguchi, Akira; Hata, Kenji; Ichida, Fumitaka; Meguro, Hiroko; Aburatani, Hiroyuki; Nishimura, Riko; Yoneda, Toshiyuki

doi:10.1074/jbc.m801774200

Cited by 457 publications

(388 citation statements)

References 31 publications

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“…Interestingly, although expression of Osx in vivo requires Runx2, BMP-2 is still able to stimulate alkaline phosphatase activity and Osx expression in Runx2-deficient cells (18). Recent data indicate that BMP-2 activates expression of Osx through Runx2-dependent as well as -independent mechanisms involving Dlx5 and Msx2 (17,19). These studies also showed that BMP-2 induction of Osx required the transcriptional activation of Dlx5 by p38 MAPKmediated phosphorylation (17,20).…”

supporting

confidence: 48%

p38 Regulates Expression of Osteoblast-specific Genes by Phosphorylation of Osterix

Ortuño¹,

Ruiz-Gaspà

Rodríguez-Carballo³

et al. 2010

Journal of Biological Chemistry

112

110

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Osterix, a zinc finger transcription factor, is specifically expressed in osteoblasts and osteocytes of all developing bones. Because no bone formation occurs in Osx-null mice, Osterix is thought to be an essential regulator of osteoblast differentiation. We report that, in several mesenchymal and osteoblastic cell types, BMP-2 induces an increase in expression of the two isoforms of Osterix arising from two alternative promoters. We identified a consensus Sp1 sequence (GGGCGG) as Osterix binding regions in the fibromodulin and the bone sialoprotein promoters in vitro and in vivo. Furthermore, we show that Osterix is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-73 and Ser-77 are the regulatory sites phosphorylated by p38. Our data also demonstrate that Osterix is able to increase recruitment of p300 and Brg1 to the promoters of its target genes fibromodulin and bone sialoprotein in vivo and that it directly associates with these cofactors through protein-protein interactions. Phosphorylation of Osterix at Ser-73/77 increased its ability to recruit p300 and SWI/SNF to either fibromodulin or bone sialoprotein promoters. We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes.Bone is a highly dynamic tissue that is constantly remodeled throughout life. Bone remodeling activity is dependent on a delicate balance between osteoclast resorption and osteoblast new bone formation. Deregulation of these two activities unleashes pathological states such as osteoporosis and osteosclerosis. Both endochondral and intramembranous ossification depends on osteoblasts that are derived from pluripotent mesenchymal stem cells that, in response to various cellular and environmental signals, commit to the osteoblast phenotype. Among them, BMPs 5 are essential for commitment and differentiation to the osteoblast lineage; they promote osteoblast differentiation in vitro and in vivo, bone regeneration, and ectopic bone formation in vivo (1-3). The BMP signal is transduced through the binding to its heteromeric cell membrane receptors (4, 5). BMP binding to receptors results in the activation of the Smad family of transcription factors, which directly regulate target gene expression (6). BMP target genes include a growing number of osteoblastdetermining transcription factors. For instance, in vivo genetic evidence as well as osteogenic induction of bone marrow mesenchymal stem cells in vitro has identified several types of transcription factors such as Id1, homeodomain proteins such as Dlx3 and Dlx5, ATF4, Runx2, and Osterix (Osx) (7-9). Runx2 and Osx have been widely accepted as master osteogenic factors because neither Runx2-nor Osx-null mice form mature osteoblasts (10, 11). Osx contains a proline-and serine-rich transactivation domain located in the N-terminal part of the protein and three zinc fingers with homology to the Sp1/Kruppel transcription factor family. Osx express...

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supporting

confidence: 48%

p38 Regulates Expression of Osteoblast-specific Genes by Phosphorylation of Osterix

Ortuño¹,

Ruiz-Gaspà

Rodríguez-Carballo³

et al. 2010

Journal of Biological Chemistry

112

110

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“…Secondly, RUNX2 directly regulates expression of osteocalcin (Matsubara et al , 2008). BMP2 is known to control the expression and functions of RUNX2 through Smad signaling, and a BMP2-Smad-RUNX2 axis in osteoblastogenesis has been established (Matsubara et al , 2008). However, our study showed that RUNX2 transcription levels in the B. mori dpp-expressing C3H10T1/2 target cells were not different from those in control cells and C3H10T1/2 cells transfected with the pCEP4 (Fig.…”

Section: Resultscontrasting

confidence: 49%

“…Osterix is thought to function downstream of RUNX2 during osteoblast differentiation (Choi et al , 2011;Matsubara et al , 2008). Recently, Matsubara et al (2008) obtained from the other 2 cell types. This result shows that the target cells expressed the B. mori dpp gene, and could be used to examine induction of osteogenic differentiation.…”

Section: Resultsmentioning

confidence: 99%

“…Osterix is also up-regulated by BMP2 during osteoblastic differentiation (Matsubara et al, 2008;Nakashima et al , 2002). Osterix is thought to function downstream of RUNX2 during osteoblast differentiation (Choi et al , 2011;Matsubara et al , 2008). Recently, Matsubara et al (2008) obtained from the other 2 cell types.…”

Section: Resultsmentioning

confidence: 99%

“…Firstly, BMP treatment significantly increases mRNA levels of RUNX2. Secondly, RUNX2 directly regulates expression of osteocalcin (Matsubara et al , 2008). BMP2 is known to control the expression and functions of RUNX2 through Smad signaling, and a BMP2-Smad-RUNX2 axis in osteoblastogenesis has been established (Matsubara et al , 2008).…”

Section: Resultsmentioning

confidence: 99%

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Functional analysis of Bombyx mori Decapentaplegic gene for bone differentiation in a mammalian cell

Park¹,

Goo²,

Choi³

et al. 2013

International Journal of Industrial Entomology

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Bone morphogenetic proteins (BMPs) belong to the transforming growth factor (TGF-b) superfamily and are involved in osteoblastic differentiation. The largest TGF-b superfamily subgroup shares genetic homology with human BMPs (hBMPs) and silkworm decapentaplegic (dpp). In addition, hBMPs are functionally interchangeable with Drosophila dpp . Bombyx mori dpp may induce bone formation in mammalian cells. To test this hypothesis, we synthesized the 1,285-base pairs cDNA of full-length B. mori dpp using total RNAs obtained from the fat body of 3-day-old of the 5 th instar larvae and cloned the cDNA into the pCEP4 mammalian expression vector. Next, B. mori dpp was expressed in C3H10T1/2 cells. The target cells transfected with the pCEP4-Bm dpp plasmid showed biological functions similar to those of osteogenic differentiation induction growth factors such as hBMPs. We determined the relative mRNA expression rates of Runt-related transcription factor 2 (RUNX2), osterix, osteocalcin, and alkaline phosphatase (ALP) to validate the osteoblast-specific differentiation effects of B. mori dpp by performing quantitative real-time RT-PCR. Interestingly, mRNA expression levels of the 3 marker genes except RUNX2, in cells expressing B. mori dpp were much higher than those in control cells and C3H10T1/2 cells transfected with pCEP4. These results suggested that B. mori dpp signaling regulates osterix expression during osteogenic differentiation via RUNX2-independent mechanisms.

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Osterix‐mCherry Expression Allows for Early Bone Detection in a Calvarial Defect Model

et al. 2019

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Acknowledgements: ERE was supported in part by a grant from NIH (R01 GM 49039) and some of the experiments by a sponsored research agreement from Sanofi. The authors acknowledge the assistance of other members of the Edelman lab, the in vivo imaging core at MIT, and the bio-medical engineering department at Sanofi. Author Contributions Statement: SES, SU and LFC and NA designed the experiments. SES, SU, LFC, and DP performed experiments. SES and NA wrote the manuscript. SES and PFM generated the Osterix-mCherry mice. ERE and NA supervised the project. All authors discussed the results and reviewed the manuscript.

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BMP2 Regulates Osterix through Msx2 and Runx2 during Osteoblast Differentiation

Cited by 457 publications

References 31 publications

p38 Regulates Expression of Osteoblast-specific Genes by Phosphorylation of Osterix

p38 Regulates Expression of Osteoblast-specific Genes by Phosphorylation of Osterix

Functional analysis of Bombyx mori Decapentaplegic gene for bone differentiation in a mammalian cell

Osterix‐mCherry Expression Allows for Early Bone Detection in a Calvarial Defect Model

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