Matrix vesicle-mediated mineralization in bone

Matrix vesicle-mediated mineralization is orchestrated by ultrastructural and biochemical events that lead to crystal nucleation and growth. Osteoblasts secrete extracellular matrix vesicles equipped with a variety of membrane transporters and enzymes, which are necessary for the initial nucleation and subsequent growth of calcium phosphate crystals. The influx of phosphate ions into the matrix vesicle is a complex process mediated by several enzymes and transporters, such as tissue nonspecific alkaline phosphatase (TNAP), ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), sodium/phosphate co-transporter type III (Pit1). The catalytic activity of ENPP1 generates pyrophosphate (PPi) using extracellular ATPs as a substrate, and the resultant PPi binds to growing hydroxyapatite crystals to prevent crystal overgrowth. However, TNAP hydrolyzes PPi into phosphate ions (PO4), a constituent of calcium phosphates, which are then transported into the matrix vesicle through Pit1. Accumulation of calcium ion (Ca) and PO4 inside matrix vesicles then induces crystalline nucleation, with calcium phosphate crystals budding off radially, puncturing the matrix vesicle’s membrane and finally growing out of it to form mineralized nodules. Apparently, mineralized nodules which are globular assemblies of needle-shaped mineral crystals retain some of those transporters and enzymes. The subsequent growth of mineralized nodules is regulated by surrounding organic compounds, finally leading to collagen mineralization. In this review, ultrastructural and biochemical aspects on matrix vesicle-mediated mineralization will be introduced.