Mechanisms that Regulate Normal Bone Mineral Deposition: A Hypothesis on the Role of Antagonistic Pathways in Preventing Hypo- and Hyper-Mineralization

摘要

Three molecules present in osteoblasts that affect PPi and Pi metabolism have been identified, by means of gene knock-out models, as affecting the controlled deposition of bone mineral, i.e., alkaline phosphatase (TNAP); PC-1 (or Npps, a nucleoside triphosphate pyrophosphate hydrolase isozyme, NTPPPH) and the ank gene product {a PPi transporter). Mice deficient in TNAP mimic the most severe forms of hypophosphatasia, i.e., perinatal and infantile hypophosphatasia. The TNAP-/- mice are growth impaired, develop epileptic seizures, apnea, and die before weaning. Skeletal preparations clearly show poor mineralization in the parietal bones, scapulae, vertebral bones, and ribs at approximately 8-10 days of age. PC-1 knockout mice develop progressive ossification of spinal and peripheral joint ligaments and also articular and meniscal cartilage calcification. A remarkably similar hypermineralizing phenotype has been found in ank/ank mice that lack a normal functioning ANK molecule. Matrix vesicles derived from primary osteoblasts from TNAP-/- hypophosphatasia mice contain increased levels of inorganic pyrophosphale (PPi), a known inhibitor of mineralization. PPi is produced by NTPPPH activity (due preferentially to the action of PC-1 in MVs) and is exported outside the eell by the action of the ANK protein. Our work centers on testing the hypotheses that TNAP's key function in bone is degradation of PPi to remove this mineralization inhibitor and provide free phosphate for apatite deposition. We further hypothesize that PC-1 and ANK are direct antagonist of TNAP-dependent matrix calcification. We are currently testing whether loss of function of PC-1 or ANK will ameliorate TNAP deficiency-associated osteomalacia in vivo.