Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: A unified model of the mechanisms of initiation of skeletal calcification

• DOI: 10.1002/jbmr.195
• Publication Date: 2010-08-04T00:43:15Z
• Authors: Manisha C Yadav; Ana Maria Sper Simão; Sonoko Narisawa; Carmen Huesa; Marc D McKee; Colin Farquharson; José Luis Millán
• Keywords: Endochondral ossification; Hypophosphatasia; Osteomalacia

Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities functions remain unclear. Alkaline phosphatase (TNAP) plays crucial role promoting mineralization the extracellular matrix restricting concentration calcification inhibitor inorganic pyrophosphate (PP(i)). Mutations in TNAP gene cause hypophosphatasia, heritable form rickets osteomalacia. Here we show that PHOSPHO1, with specificity for phosphoethanolamine phosphocholine, functional initiation ablation PHOSPHO1 function prevents skeletal Phospho1(-/-) mice display growth plate abnormalities, spontaneous fractures, bowed long bones, osteomalacia, scoliosis early life. Primary cultures tibial chondrocytes chondrocyte-derived vesicles (MVs) reduced mineralizing ability, plasma samples from levels elevated PP(i) concentrations. However, transgenic overexpression does not correct bone phenotype despite normalization levels. In contrast, double leads to complete absence perinatal lethality. We conclude has nonredundant during endochondral ossification, based on these data review current literature, propose an inclusive model involves intravesicular P(i) influx into MVs TNAP, nucleotide pyrophosphatase phosphodiesterase-1, collagen extravesicular progression