Bone Abstracts

Increased understanding of the biochemical pathways leading to MV-mediated initiation of skeletal, dental and vascular calcification has been attained through the extensive use of single and double knockout mouse models as well as via overexpression of genes by transgenesis. Our current integrated model of these pathways is compatible with the following sequence of events: MVs initiate mineral deposition by accumulation of P_i generated intravesicularly by the action of PHOSPHO1 on phosphocholine derived from sphingomyelin by the action of SMPD3, and also via the P_i transporter P_iT-1-mediated incorporation of extracellular P_i generated extravesicularly by TNAP and/or NPP1 on ATP. The extravesicular propagation of mineral onto the collagenous matrix is mainly controlled by the pyrophosphatase activity of TNAP that restricts the concentration of this potent mineralization inhibitor to establish a PP_i/P_i ratio conducive to controlled calcification. Additionally osteopontin, another potent mineralization inhibitor that binds to mineral as soon as it is exposed to the extracellular fluid, further restricts the degree of extracellular matrix ECM mineralization. Recently, we have also implicated PHOSPHO1 function in the biogenesis of MVs. However, how MVs are formed is still unclear and little is known about how apatite crystals formed within MVs propagate onto the collagenous matrix. Understanding MV biogenesis and function is critical to being able to develop rational approaches for the prevention of ectopic calcification.

Disclosure: I have received grants, consolation fees and speaker engagement fees from Alexion Pharmaceuticals. I have received a grant and consultation fees from AM Pharma.