Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X‐linked hypophosphatemia

Abstract

As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth – where calcium phosphate crystals are deposited and grow within an extracellular matrix – is essential to dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition such that teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibres (Sharpey's fibres) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins (SIBLINGs), and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here with clinical examples given, namely tissue-nonspecific alkaline phosphatase (TNAP) and phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH), respectively, where levels of local and systemic circulating mineralization determinants are perturbed. In XLH, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating SIBLING proteins such as matrix extracellular phosphoglycoprotein (MEPE) and osteopontin (OPN), and the phosphorylated peptides proteolytically released from them such as the acidic serine- and aspartate-rich motif (ASARM) peptide, may accumulate locally to impair mineralization in this disease.

Dual Role of the Trps1 Transcription Factor in Dentin Mineralization

“…Interestingly, the genes most affected by Trps1 deficiency are those associated with MVs, cellular structures that initiate the mineralization process ( Table 2). In vivo, a combined deficiency of TNAP and PHOSPHO1 (Phospho1 Ϫ/Ϫ ; Alpl ϩ/Ϫ mice), two phosphatases that are significantly downregulated in Trps1-KD cells, resulted in a significant decrease of dentin mineralization and was sufficient to almost completely deplete MVs from the mantle dentin (49). Consistent with these data from animal models, loss of TNAP and PHOSPHO1 in Trps1-deficient odontoblastic cells is associated with a decreased number of MVs.…”

“…It has been demonstrated that expression of this gene is induced in odontoblasts prior to mineralization of the dentin (12,13,49). qRT-PCR and Western analyses show that Phospho1 is also significantly down-regulated in all Trps1-deficient odontoblastic cell lines in comparison with shScr control cells (Fig.…”

<b>Enamel Defects in the </b><b><i>Alpl</i></b><b>^{- /-}</b><b>murine Model of Infantile Hypophosphatasia </b>

“…Pulp chamber expansion and thin dentin have been reported in some studies, while others declared no HPP effect on dentin formation. Enamel hypoplasia and severe tooth caries have also been reported in HPP patients (3,4).…”

Biophysical aspects of biomineralization

“…These vesicles are released from the hypertrophic chondrocytes and mature osteoblasts, the cells responsible for endochondral and membranous ossification. Hypertrophic chondrocyte differentiation is related to high tissue nonspecific alkaline phosphatase (TNAP) activity and to the synthesis and secretion of type X and II collagens by proliferating and pre-hypertrophic chondrocytes (Golub 2009;McKee et al 2013).…”