S100A4: A Novel Negative Regulator of Mineralization and Osteoblast Differentiation

Duarte, Wagner R.; Shibata, Tatsuya; Takenaga, Keizo; Takahashi, Eiki; Kubota, Kaori; Ohya, Keiichi; Ishikawa, Isao; Yamauchi, Mitsuo; Kasugai, Shohei

doi:10.1359/jbmr.2003.18.3.493

Cited by 85 publications

(90 citation statements)

References 31 publications

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“…Furthermore, the expression of S100 in osteoblastic cells was verified in various types of osteosarcomas, in which immunohistochemical staining for S100 was used to analyze the proliferating cells in osteosarcomas, and the main proliferating cells to be stained were found to be mature osteoblast-like cells (27,28). The existence of the S100 family in osteoblasts were confirmed in subsequent studies (18,29). S100 family members share a common S100 calcium-binding motif and have several regulatory functions in, not only protein phosphorylation, some enzyme activities, the dynamics of cytoskeletal components, transcription factors, and Ca 2ϩ homeostasis but also the cell proliferation and differentiation (15,16).…”

Section: The Effects Of Transient Transfection Of Pcdna-cacy Plasmid mentioning

confidence: 86%

“…S100 protein family has been known to exhibit an inhibitory role on protein phosphorylation and target intracellular proteins such as vimentin and annexin I and III (30 -32). S100A4, one of the S100 family members expressed by osteoblastic cells, is a novel negative regulator of matrix mineralization that most likely acts by modulating the process of osteoblast differentiation (29). Meanwhile, calcyclin, S100A6, interacts with tropomyosin-␣ at the intracellular level (16).…”

Section: The Effects Of Transient Transfection Of Pcdna-cacy Plasmid mentioning

confidence: 99%

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Calcyclin, a Ca2+ Ion-binding Protein, Contributes to the Anabolic Effects of Simvastatin on Bone

Hwang

Lee

Kim

et al. 2004

Journal of Biological Chemistry

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In vitro treatment with a pharmacological dose of simvastatin, a potent pro-drug of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, stimulates bone formation. In our study, simvastatin stimulated differentiation of osteoblasts remarkably in a dose-dependent manner, with minimal effect on proliferation. To identify the mediators of the anabolic effects of simvastatin on osteoblasts, we tried to identify and characterize simvastatin-induced proteins by using proteomic analysis. Calcyclin was significantly up-regulated by more than 10 times, and annexin I was also up-regulated by simvastatin. However, annexin III, vimentin, and tropomyosin were down-regulated. Up-regulated calcyclin mRNA by simvastatin was validated by reverse transcription in mouse calvarial cells. In confocal microscope analysis, green fluorescence protein-calcyclin fusion protein was ubiquitously observed in the of MC3T3-E1 cells transfected with green fluorescence protein-calcyclin cDNA containing plasmid and was quickly concentrated in the nucleus 20 min after simvastatin treatment. Overexpression of calcyclin cDNA stimulated both the proliferation and expression of alkaline phosphatase mRNA significantly, without exposure to simvastatin in MC3T3-E1 cells. However, both the rate of proliferation of the osteoblasts and the expression of alkaline phosphatase mRNA were suppressed significantly 1 day after treatment with the calcyclin-specific small interference RNA, and furthermore, simvastatin did not overcome this suppression in the small interference RNApretreated MC3T3-E1 cells. In conclusion, calcyclin is one of the candidate proteins that plays a role in osteoblastogenesis in response to simvastatin, although the precise functions of calcyclin in osteoblast remain to be verified.

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Section: The Effects Of Transient Transfection Of Pcdna-cacy Plasmid mentioning

confidence: 86%

Section: The Effects Of Transient Transfection Of Pcdna-cacy Plasmid mentioning

confidence: 99%

Calcyclin, a Ca2+ Ion-binding Protein, Contributes to the Anabolic Effects of Simvastatin on Bone

Hwang

Lee

Kim

et al. 2004

Journal of Biological Chemistry

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“…Msx2, which is a transcriptional factor with a homeobox domain, has recently been reported to be dominantly expressed in the PDL and to suppress PDL cytodifferentiation and mineralization through the inhibition of Runx2 functions (35). Another study revealed that S100A4, which is an intracellular calcium-binding protein, suppresses differentiation of PDL cells as well as osteoblasts (36,37). However, the expression of these molecules is relatively ubiquitous.…”

Section: Discussionmentioning

confidence: 99%

PLAP-1/Asporin, a Novel Negative Regulator of Periodontal Ligament Mineralization

Yamada¹,

Tomoeda²,

Ozawa³

et al. 2007

Journal of Biological Chemistry

185

189

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Periodontal ligament-associated protein-1 (PLAP-1)/asporin is a recently identified novel member of the small leucine-rich repeat proteoglycan family. PLAP-1/asporin is involved in chondrogenesis, and its involvement in the pathogenesis of osteoarthritis has been suggested. We report that PLAP-1/asporin is also expressed specifically and predominantly in the periodontal ligament (PDL) and that it negatively regulates the mineralization of PDL cells. In situ hybridization analysis revealed that PLAP-1/asporin was expressed specifically not only in the PDL of an erupted tooth but also in the dental follicle, which is the progenitor tissue of the PDL during tooth development. Overexpression of PLAP-1/asporin in mouse PDL-derived clone cells interfered with both naturally and bone morphogenetic protein 2 (BMP-2)-induced mineralization of the PDL cells. On the other hand, knockdown of PLAP-1/asporin transcript levels by RNA interference enhanced BMP-2-induced differentiation of PDL cells. Furthermore co-immunoprecipitation assays showed a direct interaction between PLAP-1/asporin and BMP-2 in vitro, and immunohistochemistry staining revealed the co-localization of PLAP-1/asporin and BMP-2 at the cellular level. These results suggest that PLAP-1/ asporin plays a specific role(s) in the periodontal ligament as a negative regulator of cytodifferentiation and mineralization probably by regulating BMP-2 activity to prevent the periodontal ligament from developing non-physiological mineralization such as ankylosis.

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“…When released into extracellular space it causes differentiation of neurons and osteoclasts (Novitskaya et al, 2000;Duarte et al, 2003). Furthermore, S100A4 acts as an angiogenic factor by stimulating motility of endothelial cells .…”

Section: Discussionmentioning

confidence: 99%

“…Motility of astrocytic tumor cells was also increased in response to S100A4 treatment (Belot et al, 2002). It has been shown that S100A4 could be released both by tumor and normal cells Duarte et al, 2003). One can propose then that when released into the extracellular space, S100A4 could create a microenvironment that facilitates invasion and motility of both endothelial and tumor cells, thus stimulating dissemination of tumor cells in the organism.…”

Section: Discussionmentioning

confidence: 99%

Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity

et al. 2004

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S100A4(mts1) protein expression has been strongly associated with metastatic tumor progression. It has been suggested as a prognostic marker for a number of human cancers. It is proposed that extracellular S100A4 accelerates cancer progression by stimulating the motility of endothelial cells, thereby promoting angiogenesis. Here we show that in 3D culture mouse endothelial cells (SVEC 4-10) respond to recombinant S100A4 by stimulating invasive growth of capillary-like structures. The outgrowth is not dependent on the stimulation of cell proliferation, but rather correlates with the transcriptional modulation of genes involved in the proteolytic degradation of extracellular matrix (ECM). Treatment of SVEC 4-10 with the S100A4 protein leads to the transcriptional activation of collagenase 3 (MMP-13) mRNA followed by subsequent release of the protein from the cells. b-Casein zymography demonstrates enhancement of proteolytic activity associated with MMP-13. This observation indicates that extracellular S100A4 stimulates the production of ECM degrading enzymes from endothelial cells, thereby stimulating the remodeling of ECM. This could explain the angiogenic and metastasis-stimulating activity of S100A4(mts1).

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S100A4: A Novel Negative Regulator of Mineralization and Osteoblast Differentiation

Cited by 85 publications

References 31 publications

Calcyclin, a Ca2+ Ion-binding Protein, Contributes to the Anabolic Effects of Simvastatin on Bone

Calcyclin, a Ca2+ Ion-binding Protein, Contributes to the Anabolic Effects of Simvastatin on Bone

PLAP-1/Asporin, a Novel Negative Regulator of Periodontal Ligament Mineralization

Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity

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