Functions of secretory calcium-binding phosphoproteins in dental mineralization

Abstract Biomineralization of skeletal and dental tissues has evolved via a suite of regulatory extracellular matrix proteins. The secretory calcium-binding phosphoproteins (SCPPs) are encoded by genes that arose by duplication. In the human genome, 23 SCPP genes have been identified, and 2 groups of SCPPs regulate dental mineralization: bone, dentin, and/or cementum matrix proteins and enamel proteins. In the past 2 decades, the functional roles of SCPPs in dental mineralization have been revealed by studies of human disorders and genetically edited mice. 5 enamel SCPPs, amelogenin (AMEL), enamelin (ENAM), ameloblastin (AMBN), odontogenic ameloblast associated (ODAM) and amelotin (AMTN), are secreted by ameloblasts during sequentially arranged stages of amelogenesis. Sequence variants in 4 of the enamel SCPP genes (AMEL, ENAM, AMBN, and AMTN) have been associated with inherited malformations of enamel, termed amelogenesis imperfecta (AI). Loss-of-function variants contribute to enamel of reduced thickness and/or mineral density. 2 bone/dentin/cementum SCPPs, dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP), are critical for dentin mineralization. Functional studies in genetically edited mice imply that dentin sialoprotein (DSP, the N-terminal fragment of DSPP) promotes the propagation of mineralization, and that dentin phosphoprotein (DPP, the C-terminal fragment of DSPP) is essential for the fusion and the increase of mineral density of calcospherites. Pathogenic variants in DSPP can cause 2 distinct entities of isolated hereditary dentinogenesis imperfecta (DGI). Bone sialoprotein (BSP) and osteopontin (OPN) are markers of cementum (and bone) in multiple species. Global ablation of BSP in mice resulted in acellular cementum hypoplasia, hypomineralized alveolar bone and breakdown of periodontal function. OPN appears to have a more complex role in regulating mineralized tissues via several direct and indirect mechanisms. Research into SCPPs has provided new insights into the evolution of biomineralization, normal dental development, and inherited disorders, as well as translational directions for tissue repair and regeneration.