MMP2-cleavage of DMP1 generates a bioactive peptide promoting differentiation of dental pulp stem/progenitor cell.
MMP2-cleavage of DMP1 generates a bioactive peptide promoting differentiation of dental pulp stem/progenitor cell.
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DOI：
10.22203/ecm.v018a08
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发表时间：
2009-11-12
影响因子：
3.1
通讯作者：
George A
中科院分区：
文献类型：
--
作者：
Chaussain C;Eapen AS;Huet E;Floris C;Ravindran S;Hao J;Menashi S;George A
牙本质基质蛋白1（Dentin Matrix Protein 1，DMP 1）在牙本质矿化过程中起调节作用，同时也是一种信号分子。基质金属蛋白酶-2（matrix metalloproteinase-2，MMP-2）是牙本质基质中的主要蛋白酶，其在牙齿形成中起重要作用，并且在龋过程中起潜在作用。本研究探讨了MMP-2切割DMP 1释放生物活性肽的可能性。DMP 1，无论是在重组形式和在其天然状态的牙本质基质内，被证明是MMP-2的底物。MMP-2对DMP 1的蛋白水解加工产生了两种主要的肽，一种含有已知携带参与生物矿化的ASARM（富含天冬氨酸和丝氨酸的结构域）结构域和DMP 1的DNA结合位点的蛋白质的C-末端区域。用重组N-和C-末端多肽模拟DMP 1的MMP-2切割产物的体外实验证明了C-多肽对牙髓干细胞/祖细胞分化为推定的成牙本质细胞表型的影响。在体内植入这种肽在大鼠损伤的牙髓模型诱导了一个均匀的牙本质桥覆盖的栅栏的定向细胞表达牙本质涎蛋白（DSP）和DMP 1的快速形成，证明了一个有效的修复过程。这些数据表明，通过MMP-2对DMP 1的蛋白水解加工产生的肽可以调节牙本质形成过程中间充质细胞的分化，从而在病理情况如龋坏中维持修复性牙本质的形成。此外，这些数据开辟了使用这种肽在损伤后再生牙本质的新治疗可能性。
Dentin Matrix Protein 1 (DMP1) plays a regulatory role in dentin mineralization and can also function as a signaling molecule. MMP-2 (matrix metalloproteinase-2) is a predominant protease in the dentin matrix that plays a prominent role in tooth formation and a potential role during the carious process. The possibility that MMP-2 can cleave DMP1 to release biologically active peptides was investigated in this study. DMP1, both in the recombinant form and in its native state within the dentin matrix, was shown to be a substrate for MMP-2. Proteolytic processing of DMP1 by MMP-2 produced two major peptides, one that contains the C-terminal region of the protein known to carry both the ASARM (aspartic acid and serine rich domain) domain involved in biomineralization and the DNA binding site of DMP1. In vitro experiments with recombinant N- and C-terminal polypeptides mimicking the MMP-2 cleavage products of DMP1 demonstrated an effect of the C-polypeptide on the differentiation of dental pulp stem/progenitor cells to a putative odontoblast phenotype. In vivo implantation of this peptide in a rat injured pulp model induced a rapid formation of a homogeneous dentin bridge covered by a palisade of orientated cells expressing dentin sialoprotein (DSP) and DMP1, attesting an efficient repair process. These data suggest that a peptide generated through the proteolytic processing of DMP1 by MMP-2 can regulate the differentiation of mesenchymal cells during dentinogenesis and thus sustain reparative dentin formation in pathological situations such as carious decay. In addition, these data open a new therapeutic possibility of using this peptide to regenerate dentin after an injury.