THE ROLE OF DMP1 IN OSTEOCYTE FUNCTION

University Of Missouri Kansas City, Kansas City MO

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Abstract

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