Phosphorylated extracellular matrix proteins, including matrix extracellular phosphoprotein (MEPE), are involved in the formation and mineralization of dental tissues. In this study, we evaluated the potential of Dentonin, a synthetic peptide derived from MEPE, to promote the formation of reparative dentin. Agarose beads, either soaked with Dentonin or unloaded, were implanted into the pulps of rat molars, and examined 8, 15, and 30 days after treatment. At day 8, Dentonin promoted the proliferation of pulp cells, as visualized by PCNA-labeling. RP59-positive osteoblast progenitors were located around the Dentonin-soaked beads. PCNA- and RP59-labeling were decreased at day 15, while osteopontin, weakly labeled at day 8, was increased at 15 days, but dentin sialoprotein was undetectable at any time. At 8 days, precocious reparative dentin formation occurred in pulps containing Dentonin-soaked beads, with formation slowing after 15 days. These results suggest that Dentonin affects primarily the initial cascade of events leading to pulp healing.
Get full access to this article
View all access options for this article.
References
1.
Argiro L, Desbarats M, Glorieux FH, Escarot B -2001-. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Genomics74:342–351.
2.
Berndt TJ, Schiavi S, Kumar R -2005-. “Phosphatonins” and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol289:F1170–F1182.
3.
Bresler D, Bruder J, Mohnike K, Fraser WD, Rowe PS -2004-. Serum MEPE-ASARM-peptides are elevated in X-linked rickets -HYP-: implications for phosphaturia and rickets. J Endocrinol183:R1–R9.
4.
Celis JE, Celis A -1985-. Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells. Subdivision of S phase. Proc Natl Acad Sci USA82:3262–3266.
5.
Decup F, Six N, Palmier B, Buch D, Lasfargues J-J, Salih E, et al. -2000-. Bone sialoprotein-induced reparative dentinogenesis in the pulp of rat’s molar. Clin Oral Investig4:110–119.
6.
Fisher LW, Fedarko NS -2003-. Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res44-Suppl 1-:33–40.
7.
Goldberg M, Smith AJ -2004-. Cells and extracellular matrices of dentin and pulp. A biological basis for repair and tissue engineering. Crit Rev Oral Biol Med15:13–27.
8.
Goldberg M, Six N, Decup F, Buch D, Soheili Madj E, Lasfargues JJ, et al. -2001-. Application of bioactive molecules in pulp-capping situations. Adv Dent Res15:91–95.
9.
Goldberg M, Lacerda–Pinheiro S, Jegat N, Six N, Septier D, Priam F, et al. -2006-. The impact of bioactive molecules to stimulate tooth repair and regeneration as part of restorative dentistry. Dent Clin North Am50:277–298.
10.
Gowen LC, Petersen DN, Mansolf AL, Qi H, Stock JL, Tkalcevic GT, et al. -2003-. Targeted disruption of the osteoblast/osteocyte factor 45 gene -OF45- results in increased bone formation and bone mass. J Biol Chem278:1998–2007.
11.
Hayashibara T, Hiraga T, Yi B, Nomizu M, Kumagai Y, Nishimura R, et al. -2004-. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. J Bone Miner Res19:455–462.
12.
Jain A, Fedarko NS, Collins MT, Gelman R, Ankrom MA, Tayback M, et al. -2004-. Serum levels of matrix extracellular phosphoglycoprotein -MEPE- in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density. J Clin Endocrinol Metab89:4158–4161.
13.
Krüger A, Ellerström C, Lundmark C, Christersson C, Wurtz T -2002-. RP59, a marker for osteoblast recruitment, is also detected in primitive mesenchymal cells, erythroid cells, and megacaryocytes. Dev Dyn223:414–418.
14.
Lacerda-Pinheiro S, Septier D, Tompkins K, Veis A, Goldberg M, Chardin H -2006-. Amelogenin gene splice products A+4 and A−4 implanted in soft tissue determine the reorientation of CD45-positive cells to an osteo-chondrogenic lineage. J Biomed Mater Res A79:1015–1022.
15.
Liu H, Li W, Gao C, Kumagai Y, Blacher RW, DenBesten PK -2004-. Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation. J Dent Res83:496–499.
16.
Liu H, Li W, Shi S, Habelitz S, Gao C, Denbesten P -2005-. MEPE is downregulated as dental pulp stem cells differentiate. Arch Oral Biol50:923–928.
17.
Liu S, Brown TA, Zhou J, Awad H, Guilak F, Quarles LD -2005-. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. J Am Soc Nephrol16:1645–1653.
18.
Lu C, Huang S, Miclau T, Helms JA, Colnot C -2004-. Mepe is expressed during skeletal development and regeneration. Histochem Cell Biol121:493–499.
19.
MacDougall M, Simmons D, Gu TT, Dong J -2002-. MEPE/OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21. Connect Tissue Res43:320–330.
20.
Nagel DE, Khosla S, Sanyal A, Rosen DM, Kumagai Y, Riggs BL -2004-. A fragment of the hypophosphatemic factor, MEPE, requires inducible cyclooxygenase-2 to exert potent anabolic effects on normal human marrow osteoblast precursors. J Cell Biochem93:1107–1114.
21.
Ogbureke KU, Fisher LW -2004-. Expression of SIBLINGs and their partner MMPs in salivary glands. J Dent Res83:664–670.
22.
Ogbureke KU, Fisher LW -2005-. Renal expression of SIBLING proteins and their partner matrix metalloproteinases -MMPs-. Kidney Int68:155–166.
23.
Petersen DN, Tkalcevic GT, Mansolf AL, Rivera-Gonzalez R, Brown TA -2000-. Identification of osteoblast/osteocyte factor -OF45-, a bone specific cDNA encoding an RGD-containing protein that is highly expressed in odontoblasts and osteocytes. J Biol Chem275:36172–36180.
24.
Qin C, Baba O, Butler WT -2004-. Post–translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis. Crit Rev Oral Biol Med15:126–136.
25.
Quarles LD -2003-. FGF23, Phex, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab285:E1–E9.
26.
Robbins BA, de la Vega D, Ogata K, Tan EM, Nakamura RM -1987-. Immunohistochemical detection of proliferating cell nuclear antigen in solid human malignancies. Arch Pathol Lab Med111:841–845.
27.
Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, et al. -2000-. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics67:54–68.
28.
Rowe PS, Garrett IR, Schwarz PM, Carnes DL, Lafer EM, Mundy GR, et al. -2005-. Surface plasmon resonance -SPR- confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets -HYP-. Bone36:33–46.
29.
Siggelkow H, Schmidt E, Hennies B, Hufner M -2004-. Evidence of downregulation of matrix extracellular phosphoglycoprotein during terminal differentiation in human osteoblasts. Bone35:570–577.
30.
Six N, Decup F, Lasfargues J-J, Salih E, Goldberg M -2002a-. Osteogenic proteins -bone sialoprotein and bone morphogenetic protein-7- and dental pulp mineralization. J Mater Sci Mater Med13:225–232.
31.
Six N, Lasfargues JJ, Goldberg M -2002b-. Differential repair responses in the coronal and radicular areas of the exposed rat molar pulp induced by recombinant human bone morphogenetic protein-7 -osteogenic protein 1-. Arch Oral Biol47:177–187.
32.
Six N, Tompkins K, Septier D, Veis A, Goldberg M -2004-. Recruitment and characterization of the cells involved in reparative dentin formation in the exposed rat molar pulp after implantation of amelogenin gene splice products A+4 and A−4. Oral Biosci Med1:35–44.
33.
Wurtz T, Krüger A, Christersson C, Lundmark C -2001-. A new protein expressed in bone marrow cells and osteoblasts with implication in osteoblast recruitment. Exp Cell Res263:236–242.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
