Phosphate/pyrophosphate and MV-related proteins in mineralisation: discoveries from mouse models

Abstract

During the process of matrix vesicle (MV)-mediated initiation of mineralisation, chondrocytes and osteoblasts mineralise the extracellular matrix by promoting the seeding of basic calcium phosphate crystals of hydroxyapatite (HA) along the collagen fibrils. This orchestrated process is carefully regulated by the balanced action of propagators and inhibitors of calcification. The primary antagonistic regulators of extracellular matrix mineralisation are phosphate (Pi) and inorganic pyrophosphate (PPi). Studies in mouse models and in humans have established critical roles for Pi/PPi homeostasis in biomineralisation. In this review, we present the regulators of Pi/PPi, as derived from animal models, and discuss their clinical relevance to physiological and pathological mineralisation.

Keywords: MV-related proteins; Matrix vesicles; Mineralisation; OPN.; PPi; Pi.

Figure 1

Schematic representation of Pi/PPi regulators involved in MV-mediated mineralisation. The HA crystals are composed of Pi and Ca²⁺. In the MVs, Pi is generated by the function of PiT1/2 phosphate transporters, as well as by the hydrolysis of the phosphomonoesters PEA and PChol by the phosphatase PHOSPHO1. Ca²⁺ transport is mediated by annexin channels that allow influx into the vesicles. The ePPi pool is derived both by NPP1 catalysing production from eATP and by intracellular export via the ANK transporter at the level of the chondrocyte and osteoblast membranes. For both TNSALP and NPP1, ATPase, ADPase and PPiase contribute to the ePi pool, though TNSALP is more efficient than NPP1 at the level of the MVs. Moreover, a negative feedback loop exists in intracellular. PPi, which is produced by NPP1 and transported by ANK, inhibits the expression of Enpp1 and Ank. PPi, together with its induction of OPN expression, inhibit HA crystal propagation and growth.