Osteogenic transcription factors and proto-oncogene regulate bone sialoprotein gene transcription

Takai, Hideki; Mezawa, Masaru; Choe, Jin; Nakayama, Yohei; Ogata, Yorimasa

doi:10.2334/josnusd.55.209

Cited by 5 publications

(3 citation statements)

References 55 publications

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“…RNA was extracted for qRT-PCR for the gene indicated (18S normalized). A : Note that increases in early osteogenic ( Msx1 , Msx2 , Dlx5 ) ( 47 , 48 ), osteochondrogenic ( Sox9 ) ( 35 ), adipogenic ( PPARG ) ( 49 ), and smooth muscle myogenic ( 50 ) ( Myocd ) transcriptional regulators were reduced in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR −/− myofibroblasts vs. Msx1(fl/fl);Msx2(fl/fl);LDLR −/− controls. B : Shh and Sca1 , markers of the early multipotent adventitial progenitor ( 26 ), were also reduced in Msx -deficient myofibroblasts.…”

Section: Resultsmentioning

confidence: 99%

Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets

et al. 2014

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When fed high-fat diets, male LDLR−/− mice develop obesity, hyperlipidemia, hyperglycemia, and arteriosclerotic calcification. An osteogenic Msx-Wnt regulatory program is concomitantly upregulated in the vasculature. To better understand the mechanisms of diabetic arteriosclerosis, we generated SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− mice, assessing the impact of Msx1+Msx2 gene deletion in vascular myofibroblast and smooth muscle cells. Aortic Msx2 and Msx1 were decreased by 95% and 34% in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− animals versus Msx1(fl/fl);Msx2(fl/fl);LDLR−/− controls, respectively. Aortic calcium was reduced by 31%, and pulse wave velocity, an index of stiffness, was decreased in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− mice vs. controls. Fasting blood glucose and lipids did not differ, yet SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− siblings became more obese. Aortic adventitial myofibroblasts from SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− mice exhibited reduced osteogenic gene expression and mineralizing potential with concomitant reduction in multiple Wnt genes. Sonic hedgehog (Shh) and Sca1, markers of aortic osteogenic progenitors, were also reduced, paralleling a 78% reduction in alkaline phosphatase (TNAP)–positive adventitial myofibroblasts. RNA interference revealed that although Msx1+Msx2 supports TNAP and Wnt7b expression, Msx1 selectively maintains Shh and Msx2 sustains Wnt2, Wnt5a, and Sca1 expression in aortic adventitial myofibroblast cultures. Thus, Msx1 and Msx2 support vascular mineralization by directing the osteogenic programming of aortic progenitors in diabetic arteriosclerosis.

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Section: Resultsmentioning

confidence: 99%

Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets

et al. 2014

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“…Matrix metalloprotease family members such as MMP2, MMP3, and MMP13 are also known to be increased in PyMT tumors [ 76 , 78 ]. Interestingly, a large cassette of these genes are directly or indirectly associated with transcriptional regulators including RUNX2 [ 17 , 79 , 80 ]. Thus, it would not be surprising that tumor growth was delayed in CADD522-treated MMTV-PyMT mice.…”

Section: Discussionmentioning

confidence: 99%

Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity

et al. 2017

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The RUNX2 transcription factor promotes breast cancer growth and metastasis through interactions with a variety of cofactors that activate or repress target genes. Using a direct drug discovery approach we identified CADD522 as a small molecule that inhibits the DNA binding of the runt box domain protein, RUNX2. The current study defines the effect of CADD522 on breast cancer growth and metastasis, and addresses the mechanisms by which it exerts its anti-tumor activity.CADD522 treatment resulted in significant growth inhibition, clonogenic survival, tumorsphere formation, and invasion of breast cancer cells. CADD522 negatively regulated transcription of RUNX2 target genes such as matrix metalloproteinase-13, vascular endothelial growth factor and glucose transporter-1, but upregulated RUNX2 expression by increasing RUNX2 stability. CADD522 reduced RUNX2-mediated increases in glucose uptake and decreased the level of CBF-β and RUNX2 phosphorylation at the S451 residue. These results suggest several potential mechanisms by which CADD522 exerts an inhibitory function on RUNX2-DNA binding; interference with RUNX2 for the DNA binding pocket, inhibition of glucose uptake leading to cell cycle arrest, down-regulation of CBF-β, and reduction of S451-RUNX2 phosphorylation.The administration of CADD522 into MMTV-PyMT mice resulted in significant delay in tumor incidence and reduction in tumor burden. A significant decrease of tumor volume was also observed in a CADD522-treated human triple-negative breast cancer-patient derived xenograft model. CADD522 impaired the lung retention and outgrowth of breast cancer cells in vivo with no apparent toxicity to the mice. Therefore, by inhibiting RUNX2-DNA binding, CADD522 may represent a potential antitumor drug.

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“…Runx2, Dlx5 and c-Src might be crucial transcriptional regulators of mineralization and bone formation (Takai et al, 2013). But previous results reported by other groups it is unknown whether another transcription factor, Osterix, can be regulated by nonreceptor tyrosine kinase, c-Src.…”

Section: Introductionmentioning

confidence: 98%

Src enhances osteogenic differentiation through phosphorylation of Osterix

Choi

Han

Lee

et al. 2015

Molecular and Cellular Endocrinology

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Osteogenic transcription factors and proto-oncogene regulate bone sialoprotein gene transcription

Cited by 5 publications

References 55 publications

Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets

Targeted Reduction of Vascular Msx1 and Msx2 Mitigates Arteriosclerotic Calcification and Aortic Stiffness in LDLR-Deficient Mice Fed Diabetogenic Diets

Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity

Src enhances osteogenic differentiation through phosphorylation of Osterix

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