Biomineralization and matrix vesicles in biology and pathology

Abstract

In normal healthy individuals, mineral formation is restricted to specialized tissues which form the skeleton and the dentition. Within these tissues, mineral formation is tightly controlled both in growth and development and in normal adult life. The mechanism of calcification in skeletal and dental tissues has been under investigation for a considerable period. One feature common to almost all of these normal mineralization mechanisms is the elaboration of matrix vesicles, small (20-200 nm) membrane particles, which bud off from the plasma membrane of mineralizing cells and are released into the pre-mineralized organic matrix. The first crystals which form on this organic matrix are seen in and around matrix vesicles. Pathologic ectopic mineralization is seen in a number of human genetic and acquired diseases, including calcification of joint cartilage resulting in osteoarthritis and mineralization of the cardiovasculature resulting in exacerbation of atherosclerosis and blockage of blood vessels. Surprisingly, increasing evidence supports the contention that the mechanisms of soft tissue calcification are similar to those seen in normal skeletal development. In particular, matrix vesicle-like membranes are observed in a number of ectopic calcifications. The purpose of this review is to describe how matrix vesicles function in normal mineral formation and review the evidence for their participation in pathologic calcification.

Fig. 1

Transmission electron micrograph of the mineralization front (MF) in forming bone. An osteoblast (OB) is secreting matrix including collagen (C). A matrix vesicle (MV) with mineral is seen in the matrix

Fig. 2

A schematic representation of the regulation of Ca²⁺ and Pi concentration in the extracellular matrix by cells and MV. Intracellular nucleotide triphosphates (iNTP) contribute to the intracellular Pi pool through enzymatic hydrolysis (ATPase) and the intracellular pyrophosphate pool (iPPi) by enzymes which produce nucleotide monophosphates (NMPsyn). iPPi also feeds the Pi pool by hydrolysis by intracellular pyrophosphatase (iPPase). iPPi is transported into the matrix via the progressive ankylosis protein (ANK). iNTPs also are secreted into the matrix to form a pool of extracellular NTPs (eNTP). eNTPs are converted by MV enzyme nucleotide pyrophosphohydrolase (NPP1) to ePPi, and ePPI is broken down to Pi by MV enzyme tissue nonspecific alkaline phosphatase (TNAP). In the matrix, Ca²⁺ and PI combine to form hydroxyapatite (HA)