MMP2-cleavage of DMP1 generates a bioactive peptide promoting differentiation of dental pulp stem/progenitor cell

Abstract

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.

Abnormal Presence of the Matrix Extracellular Phosphoglycoprotein-Derived Acidic Serine- and Aspartate-Rich Motif Peptide in Human Hypophosphatemic Dentin

“…In this model, a reparative dentin bridge was formed within a time lapse of 1 month to serve as a protective barrier to the dental pulp. 25,26 We were able to report that P-ASARM peptide impaired the formation of the reparative dentin bridge classically observed in our model. The peptide induced abnormal purple-stained fibrous areas in the greenstained neo-formed dentin bridge that somehow evoked unmineralized interglobular spaces observed in hypophosphatemic human dentin.…”

“…25,26 The beads were implanted in the pulp of the first upper jaw molar of 12 rats (6 weeks, OFA/SD Charles River, Lyon, France). In brief, after gingival electrosurgery, half-moon-shaped class V 0.5-mm cavities were prepared on the mesial aspect of the first maxillary molars using a 0.2-mm diameter round bur (E0123, Dentsply Maillefer, Ballaigues, Switzerland).…”

Retraction: Products of dentin matrix protein-1 degradation by interleukin-1β-induced matrix metalloproteinase-3 promote proliferation of odontoblastic cells

“…Another concern of the present study is that IL-1β-induced MMPs, except for MMP-3, are required for cell proliferation. A peptide generated through the proteolytic processing of DMP-1 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 (41). However, we confirmed that there was no significant increase in MMP-2 mRNA in response to IL-1β-induced odontoblastlike cells derived from ESCs and KN-3 cells (data not shown).…”

Inflammation–regeneration interplay in the dentine–pulp complex

“…TIMP-1) are also synthesized by odontoblasts and subsequently sequestered in the dentine matrix. 24 As MMPs are known to be important biological activators of SIBLINGs and growth factors, 37 the presence and release of bioactive forms of MMPs from dentine further highlight the regulatory potential of dentine breakdown products in signaling tertiary dentinogenesis and dental tissue regeneration.…”