Exploration of the ectophosphodiesterase NPP1 as a target for the treatment of calcification diseases.

The integral membrane protein NPP1 (Nucleotide Pyrophosphatase/Phosphodiesterase-1) generates PPi by the hydrolysis of extracellular ATP. PPi is an inhibitor of calcification in soft tissues and prevents the disproportionate accumulation of hydroxyapatite in bones. An excess of PPi results in the deposition of pathological calcium pyrophosphate dihydrate crystals (chondrocalcinosis), but also contributes to the development of hypophosphatasia, which is characterized by poorly mineralized bones. With the current project we explore the therapeutic potential of NPP1 inhibitors in mouse models for hypophosphatasia and chondrocalcinosis, using small-molecule inhibitors and inhibitory antibodies. Our specific research goals are (1) to optimize recently identified small-molecule inhibitors of NPP1 and to generate inhibitory monoclonal NPP1 antibodies, (2) to co-crystallize NPP1 with a small-molecule inhibitor and determine its detailed 3D-structure, (3) to generate a transgenic mouse that overexpresses NPP1 in postnatal articular cartilage, as a potential model for chondrocalcinosis, and (4) to test selected NPP1 inhibitors in cell-based calcification assays and in mouse models for hypophosphatasia and chondrocalsinosis.

Keywords:Hypophosphatasia, Chondrocalcinosis, NPP1, Nucleotide Pyrophosphatase/Phosphodieste, Calcification

Disciplines:Orthopaedics