Dentin Matrix Protein 1, DMP1, was originally identified from dentin, however, DMP1 is expressed in othercells within the skeleton with highest amounts in the osteocyte. DMP1 protein is localized along the laminalimitans, the canalicular walls of the osteocyte and increases dramatically in response to mechanical loadboth in vitro and in vivo. DMP1 null mice exhibit an osteomalacic phenotype with a dramatic increase inosteoid. Boney protrusions occur at sites of muscle attachment with age. There is severe impairment inmineralization and an apparent delay in differentiation and maturation of the osteoblast into a matureosteocyte. Osteocytes within the mineralized portion of the bone show several abnormalities. Lacunar sizeis increased 2 fold with fewer dendrites and the inner surface of the lacunae and canaliculi is irregularcompared to smooth lacunae in normal mice. Osteocytes within osteoid show a loss of the lamina limitanswith a concomitant obliteration of the canalicular space and abnormal 'buckling' of the membrane surface ofdendrites. None of these osteocyte abnormalities were observed in another model of osteomalacia, thevitamin D receptor knockout, nor could the DMP1 null phenotype be rescued by a high calcium, phosphatediet suggesting that the defect is not systemic. Based on these observations, the following hypothesis hasbeen proposed: DMP1 is essential for the transition of osteoblasts/preosteocytes to osteocytes, for formationand maintenance of the lacuno-canalicular system, and in regulation of osteocyte-mediated responses tomechanical loading. To address this hypothesis, three specific aims are proposed: 1) to determine the roleof DMP1 in the osteoblast-to-osteocyte transition and formation and maintenance of the lacuno-canalicularsystem, 2) to determine the effects of loading and unloading on the Dmp1 null skeleton, and 3) to determinethe role of DMP1 in the function of the mature osteocyte and its response to load. The availability of Dmp1-null mice and newly developed technologies for investigating osteocyte morphology and function providepowerful approaches with which to dissect out the specific role of DMP1 in osteocyte function and inmechanical response to load both in vitro and in vivo. These studies may highlight novel pathways formechanical stimulation in osteocytes that could be targeted in the treatment of metabolic bone diseases.
Showing the most recent 10 out of 97 publications
