THE ROLE OF DMP1 IN OSTEOCYTE FUNCTION

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Dentin Matrix Protein 1, DMP1, was originally identified from dentin, however, DMP1 is expressed in other cells within the skeleton with highest amounts in the osteocyte. DMP1 protein is localized along the lamina limitans, the canalicular walls of the osteocyte and increases dramatically in response to mechanical load both in vitro and in vivo. DMP1 null mice exhibit an osteomalacic phenotype with a dramatic increase in osteoid. Boney protrusions occur at sites of muscle attachment with age. There is severe impairment in mineralization and an apparent delay in differentiation and maturation of the osteoblast into a mature osteocyte. Osteocytes within the mineralized portion of the bone show several abnormalities. Lacunar size is increased 2 fold with fewer dendrites and the inner surface of the lacunae and canaliculi is irregular compared to smooth lacunae in normal mice. Osteocytes within osteoid show a loss of the lamina limitans with a concomitant obliteration of the canalicular space and abnormal "buckling" of the membrane surface of dendrites. None of these osteocyte abnormalities were observed in another model of osteomalacia, the vitamin D receptor knockout, nor could the DMP1 null phenotype be rescued by a high calcium, phosphate diet suggesting that the defect is not systemic. Based on these observations, the following hypothesis has been proposed: DMP1 is essential for the transition of osteoblasts/preosteocytes to osteocytes, for formation and maintenance of the lacuno-canalicular system, and in regulation of osteocyte-mediated responses to mechanical loading. To address this hypothesis, three specific aims are proposed: 1) to determine the role of DMP1 in the osteoblast-to-osteocyte transition and formation and maintenance of the lacuno-canalicular system, 2) to determine the effects of loading and unloading on the Dmp1 null skeleton, and 3) to determine the 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 provide powerful approaches with which to dissect out the specific role of DMP1 in osteocyte function and in mechanical response to load both in vitro and in vivo. These studies may highlight novel pathways for mechanical stimulation in osteocytes that could be targeted in the treatment of metabolic bone diseases.