Association of the –381T/C promoter variation of the brain natriuretic peptide gene with low bone-mineral density and rapid postmenopausal bone loss

Kajita, Mitsuko; Ezura, Yoichi; Iwasaki, Hiromichi; Ishida, Ryota; Yoshida, Hideyo; Kodaira, Mina; Suzuki, Takao; Hosoi, Takayuki; Inoue, Satoshi; Shiraki, Masataka; Orimo, Hajime; Emi, Mitsuru

doi:10.1007/s100380300010

Cited by 17 publications

(12 citation statements)

References 22 publications

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“…Moreover, similar findings on the linkage of mouse chromosome 4q, syntenic to the human 1p region, to low BMD were also reported previously (75,76). Ongoing screenings for susceptibility genes that reside at the 1p36 locus identified several candidates, including TNFRSF1B (77), NPPB (78), MTHFR (79), WNT4, and ZBTB40 (45), suggesting that multiple genes, individually or in combination, contribute to the 1p36-associated low-BMD phenotype (80). It is therefore tempting to speculate, based on the findings described in this study, that RUNX3 deficiency might also affect human bone mineralization and thus may constitute a risk factor for low BMD/osteopenia in humans.…”

Section: Discussionsupporting

confidence: 73%

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

Bauer

Sharir

Kimura

et al. 2015

Molecular and Cellular Biology

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bCongenital osteopenia is a bone demineralization condition that is associated with elevated fracture risk in human infants. Here we show that Runx3, like Runx2, is expressed in precommitted embryonic osteoblasts and that Runx3-deficient mice develop severe congenital osteopenia. Runx3-deficient osteoblast-specific (Runx3 fl/fl /Col1␣1-cre), but not chondrocyte-specific (Runx3 fl/fl /Col1␣2-cre), mice are osteopenic. This demonstrates that an osteoblastic cell-autonomous function of Runx3 is required for proper osteogenesis. Bone histomorphometry revealed that decreased osteoblast numbers and reduced mineral deposition capacity in Runx3-deficient mice cause this bone formation deficiency. Neonatal bone and cultured primary osteoblast analyses revealed a Runx3-deficiency-associated decrease in the number of active osteoblasts resulting from diminished proliferation and not from enhanced osteoblast apoptosis. These findings are supported by Runx3-null culture transcriptome analyses showing significant decreases in the levels of osteoblastic markers and increases in the levels of Notch signaling components. Thus, while Runx2 is mandatory for the osteoblastic lineage commitment, Runx3 is nonredundantly required for the proliferation of these precommitted cells, to generate adequate numbers of active osteoblasts. Human RUNX3 resides on chromosome 1p36, a region that is associated with osteoporosis. Therefore, RUNX3 might also be involved in human bone mineralization.

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Section: Discussionsupporting

confidence: 73%

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

Bauer

Sharir

Kimura

et al. 2015

Molecular and Cellular Biology

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“…Some of these genes likely promote osteoblast differentiation and bone formation, and indeed treatment of isolated osteoblasts with estrogens has been shown to inhibit the osteoblast phenotype [29]. For example, similar to Osteoclacin [21], we report here that E2 antagonizes RUNX2-mediated stimulation of, Prdm4 and Nppb (Figure 5), which may play a role in RUNX2-driven osteoblastogenesis [56–58] and possibly in postmenopausal osteoporosis [59]. We also report here that E2 ablates RUNX2-mediated stimulation of Pstpip2 (Figure 5), which is highly homologous to Imp2, the product of which plays a critical role in Fission Yeast membrane trafficking [60].…”

Section: 0 - Discussionsupporting

confidence: 55%

“…Future studies are warranted to directly test the role of RUNX2 and its target genes (e.g., Pstpip2 , Vwa7 ) as mediators of the anti-osteoclastogenic property of estrogens, and weigh them against alternative anti-resorptive mechanisms of action of estrogens, such as the stimulation of Fasl and Mmp3 [39, 56]. [56] [57] [58] [59] [60] [61]…”

Section: 0 - Discussionmentioning

confidence: 99%

Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association

Martín

Xiong

Koromila

et al. 2015

Bone

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In addition to its thoroughly investigated role in bone formation, the osteoblast master transcription factor RUNX2 also promotes osteoclastogenesis and bone resorption. Here we demonstrate that 17β-estradiol (E2), which is known to attenuate bone turnover in vivo and RUNX2 activity in vitro, strongly inhibits RUNX2-mediated osteoblast-driven osteoclastogenesis in co-cultures. Towards deciphering the underlying mechanism, we induced premature expression of RUNX2 in primary murine pre-osteoblasts, which resulted in robust differentiation of co-cultured splenocytes into mature osteoclasts. This was attributable to RUNX2-mediated increase in RANKL secretion, determined by ELISA, as well as to RUNX2-mediated increase in RANKL association with the osteoblast membrane, demonstrated using confocal fluorescence microscopy. The increased association with the osteoblast membrane was recapitulated by transiently expressed GFP-RANKL. E2 abolished the RUNX2-mediated increase in membrane-associated RANKL and GFP-RANKL, as well as the concomitant osteoclastogenesis. RUNX2-mediated RANKL cellular redistribution was attributable in part to a decrease in Opg expression, but E2 did not influence Opg expression either in the presence or absence of RUNX2. Diminution of RUNX2-mediated osteoclastogenesis by E2 occurred regardless of whether the pre-osteoclasts were derived from wild type or estrogen receptor alpha (ERα)-knockout mice, suggesting that activated ERα inhibited osteoblast-driven osteoclastogenesis by acting in osteoblasts, possibly targeting RUNX2. Furthermore, the selective ER modulators (SERMs) tamoxifen and raloxifene mimicked E2 in abrogating the stimulatory effect of osteoblastic RUNX2 on osteoclast differentiation in the co-culture assay. Thus, E2 antagonizes RUNX2-mediated RANKL trafficking and subsequent osteoclastogenesis. Targeting RUNX2 and/or downstream mechanisms that regulate RANKL trafficking may lead to the development of improved SERMs and possibly non-hormonal therapeutic approaches to high turnover bone disease.

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“…To our knowledge, this gene has not been linked to the process of tumorigenesis before. However, accumulating evidence suggests that natriuretic peptides also have a role outside the cardiovascular system, and they have been reported to be important regulators of bone and cartilage differentiation and maintenance; that is, overexpression of BNP results in skeletal overgrowth in transgenic mice (Suda et al , 1998), and variations in the promoter of NPPB is linked to rapid bone loss (Kajita et al , 2003). In agreement with a regulative role of NPPB in bone differentiation and growth, dysregulation of this gene might be associated with impaired differentiation in cancer.…”

Section: Discussionmentioning

confidence: 99%

Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes

et al. 2013

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Background:Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations.Methods:To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling.Results:The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes—COL1A2, KYNU, ACTG2 and NPPB—were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease.Interpretation:The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is the first time that expression profiles are associated with functional characteristics of osteosarcoma cell lines.

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Association of the –381T/C promoter variation of the brain natriuretic peptide gene with low bone-mineral density and rapid postmenopausal bone loss

Cited by 17 publications

References 22 publications

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association

Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes

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