Domain of Dentine Sialoprotein Mediates Proliferation and Differentiation of Human Periodontal Ligament Stem Cells

Alkan, Özlem; Yuan, Guohua; Yang, Guobin; Wang, Feng; Li, Wentong; Yang, Yuan; Guo, Feng; Gao, Qiannan; Shoff, Lisa; Chen, Zhi; Gay, Isabel; Donly, Kevin J.; MacDougall, Mary; Chen, Shuo

doi:10.1371/journal.pone.0081655

Cited by 36 publications

(37 citation statements)

References 72 publications

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“…Consistent with our gene expression data ( Fig. 4 ), a few studies have reported that overexpression of DSPP or an exogenous rC-DSP treatment increased the expression of osteogenic markers including Runx2 and Osx [31] , [32] . Thus, it is possible to suggest that the DSP portion within DSPP protein may play a modulatory role in cellular functions, i.e.…”

Section: Discussionsupporting

confidence: 91%

“…In their studies, rhDSP treatment induces type I collagen [29] and DSPP [30] upregulation in human dental pulp cells. More recently, it has been reported that the recombinant mouse C-terminal DSP fragment (rC-DSP, residues from 183 to 457) produced in bacteria enhances cell proliferation in human periodontal ligament (PDL) cells and PDL stem cells [31] . Consistent with our gene expression data ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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N-terminal Dentin Sialoprotein fragment induces type I collagen production and upregulates dentinogenesis marker expression in osteoblasts

Jaha

Husein

Ohyama

et al. 2016

Biochemistry and Biophysics Reports

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Bone and dentin are mineralized extracellular matrices produced by osteoblasts and odontoblasts, respectively, and their major organic portion is type I collagen. Dentinogenesis Imperfecta (DGI) is one of the most common clinically- and genetically-based disturbances of dentin formation, causing irreversible dentin defects. Among several types of DGI, patients with DGI type II exhibit opalescent dentin with partial or complete pulp obliteration. It has been previously reported that the non-sense mutation (c.133C>T) in Dentin Sialophosphoprotein (DSPP) was identified in DGI type II patients at glutamine residue 45, resulting in the premature stop codon (p.Q45X). DSPP is known to be synthesized as a single gene product and further processed at Gly462-Asp463, resulting in the production of Dentin Sialoprotein (DSP) and Dentin Phosphoprotein (DPP). We hypothesized that the shorter form (Q45X) of N-terminal Dentin Sialoprotein (N-DSP) may cause over-production of type I collagen protein as obliterated pulp is occupied by dentin. To test this hypothesis, we generated mouse recombinant Glutathione-S-Transferase (GST)-N-DSP fusion protein, and the effect of GST-N-DSP was investigated in calvarial bone explant culture and MC3T3-E1 osteoblastic culture systems. Here we show that a significant increase in calvarial bone formation is observed by GST-N-DSP. GST-N-DSP accelerates MC3T3-E1 osteoblast cell growth and proliferation and subsequent osteoblast differentiation by inducing the expression of certain osteogenic markers such as type I collagen, Runx2, Osterix and ATF4. Interestingly, GST-N-DSP significantly enhances dentinogenesis marker gene expression including Dspp and Dmp1 gene expression in non-odontogenic MC3T3-E1 cells. To rule out any artificial effect of GST-tag, we also used the synthetic peptide of N-DSP and confirmed the results of N-DSP peptide were essentially similar to those of GST-N-DSP. Taken together, our data suggest that N-DSP promotes bone formation by accelerating osteoblast cell proliferation and subsequent osteoblast differentiation accompanied by marked up-regulation of the dentin matrix markers, such as Dspp and Dmp1 genes.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

N-terminal Dentin Sialoprotein fragment induces type I collagen production and upregulates dentinogenesis marker expression in osteoblasts

Jaha

Husein

Ohyama

et al. 2016

Biochemistry and Biophysics Reports

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“…Mutations of the DSP domain cause DGI-II, DGI-III and DD-II 7 8 9 10 11 . We and other laboratories reported that full-length and COOH-terminal DSPs regulate bone/tooth related gene expression and stimulate kinase phosphorylation and dental mesenchymal differentiation 29 30 . However, the molecular mechanisms of DSP in regulating intracellular signal pathways remain unclear.…”

Section: Discussionmentioning

confidence: 79%

“…By contrast, DSP does not contain any RGD domains 9 . Evidence suggests that DSP and peptides derived from DSP regulate gene expression and protein phosphorylation and induce dental primary/stem cell differentiation 29 30 . However, the molecular mechanisms of the DSP control of gene expression and cell differentiation are not well understood.…”

mentioning

confidence: 99%

The Dentin Sialoprotein (DSP) Domain Regulates Dental Mesenchymal Cell Differentiation through a Novel Surface Receptor

Wan

Yuan

Luo

et al. 2016

Sci Rep

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Dentin sialophosphoprotein (DSPP) is a dentin extracellular matrix protein that is processed into dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP). DSP is mainly expressed in odontoblasts. We hypothesized that DSP interacts with cell surface receptors and subsequently activates intracellular signaling. Using DSP as bait for screening a protein library, we demonstrate that DSP acts as a ligand and binds to integrin β6. The 36 amino acid residues of DSP are sufficient to bind to integrin β6. This peptide promoted cell attachment, migration, differentiation and mineralization of dental mesenchymal cells. In addition, DSP aa183-219 stimulated phosphorylation of ERK1/2 and P38 kinases. This activation was inhibited by an anti-integrin β6 antibody and siRNA. Furthermore, we demonstrate that this DSP fragment induces SMAD1/5/8 phosphorylation and nuclear translocation via ERK1/2 and P38 signaling. SMAD1/5/8 binds to SMAD binding elements (SBEs) in the DSPP gene promoter. SBE mutations result in a decrease in DSPP transcriptional activity. Endogenous DSPP expression was up-regulated by DSP aa183-219 in dental mesenchymal cells. The data in the current study demonstrate for the first time that this DSP domain acts as a ligand in a RGD-independent manner and is involved in intracellular signaling via interacting with integrin β6. The DSP domain regulates DSPP expression and odontoblast homeostasis via a positive feedback loop.

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“…DPP, initiates and modulates the formation and growth of hydroxyapatite crystals during dentin formation while DSP regulates the initiation of dentin mineralization . Furthermore, recently published reports indicate that mouse carboxy‐terminal DSP enhanced the attachment, migration, proliferation, and differentiation of human periodontal ligament stem cells, regulating gene expression of teeth and bone markers, growth factors, and transcription . The precise role of DGP is yet to be fully understood.…”

Section: Introductionmentioning

confidence: 99%

Survey of dentin sialophosphoprotein and its cognate matrix metalloproteinase‐20 in human cancers

et al. 2019

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Background Matrix metalloproteinases‐20 (MMP20) expression is widely regarded as tooth specific, with expression limited to dental hard tissues. Recently, we reported MMP20 expression and interaction with dentin sialophosphoprotein (DSPP), a member of the Small Integrin Binding Ligand N‐linked Glycoproteins (SIBLINGs), in human oral squamous cell carcinoma (OSCC) and dysplastic oral premalignant lesions (OPLs), suggesting a role for MMP20‐DSPP interaction in oral carcinogenesis. Methods This study aimed to survey the expression of MMP20 and its cognate DSPP partner in the breast, colon, prostate, thyroid, and cervical neoplasms. Using commercially available tissue microarrays (TMAs) and cell lines, we performed immunohistochemistry, immunofluorescence, proximity ligation assay, and western blot experiments to determine the expressions of MMP20 and DSPP in the breast, colon, prostate, thyroid, cervical neoplasms, and their normal counterparts. Results Significantly high expression levels of MMP20 and DSPP were observed in the malignant breast, colon, prostate, thyroid, and cervical neoplasms compared with their benign and normal counterparts. Furthermore, MMP20 levels increased with advanced stages of colon and thyroid cancers. DSPP expression increased significantly with tumor stage in all cancers examined. Conclusions The co‐localization and potential MMP20‐DSPP interaction previously reported in oral cancers are present in other cancers. These results suggest MMP20‐DSPP pairing as a potential marker of disease activity in some epithelial cancers with diagnostic and prognostic implications.

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Domain of Dentine Sialoprotein Mediates Proliferation and Differentiation of Human Periodontal Ligament Stem Cells

Cited by 36 publications

References 72 publications

N-terminal Dentin Sialoprotein fragment induces type I collagen production and upregulates dentinogenesis marker expression in osteoblasts

N-terminal Dentin Sialoprotein fragment induces type I collagen production and upregulates dentinogenesis marker expression in osteoblasts

The Dentin Sialoprotein (DSP) Domain Regulates Dental Mesenchymal Cell Differentiation through a Novel Surface Receptor

Survey of dentin sialophosphoprotein and its cognate matrix metalloproteinase‐20 in human cancers

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