PLA₂ and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization

Mineralization is a key process in the formation of bone and cartilage in vertebrates, involving the deposition of calcium and phosphate containing hydroxyapatite (HA) mineral within a collagenous matrix. Inorganic phosphate (P_i) accumulation within matrix vesicles (MVs) is a fundamental stage in the precipitation of HA, with PHOSPHO1 being identified as the principal enzyme acting to produce P_i. PHOSPHO1 is a dual specific phosphocholine/phosphoethanolamine phosphatase enriched in mineralizing cells and within MVs. However, the source and mechanism by which PHOSPHO1 substrates are formed prior to mineralization has not been determined. Here we propose that two enzymes phospholipase A2 (PLA₂) and ectonucleotide pyrophophatase/phosphodiesterase 6 (ENPP6) act in sequence upon phosphatidylcholine found in MV membranes to produce phosphocholine, which PHOSPHO1 can hydrolyze to liberate P_i. This hypothesis is supported by evidence that both enzymes are expressed in mineralizing cells and data showing that phosphatidylcholine is broken down in MVs during mineralization. PLA₂ and ENPP6 activities may therefore represent a key step in the mineralization process. Further functional studies are urgently required to examine their specific roles in the initiation of skeletal mineralization.