THE ROLE OF DMP1 IN OSTEOCYTE FUNCTION

牙本质基质蛋白1（Dentin Matrix Protein 1，DMP 1）最初是从牙本质中鉴定的，然而，DMP 1在其他牙本质中表达。 骨细胞中含量最高的细胞。DMP 1蛋白定位于沿着板层 limitans，骨细胞的小管壁，并在响应机械负荷时急剧增加 无论是在体外还是在体内。DMP 1敲除小鼠表现出骨软化表型， 类骨质随着年龄的增长，肌肉附着部位会出现骨突起。严重损害， 矿化和成骨细胞分化和成熟明显延迟， 骨细胞骨的矿化部分内的骨细胞显示出几种异常。腔隙大小 骨陷窝和骨小管的内表面不规则， 与正常小鼠的光滑陷窝相比。类骨质内的骨细胞显示界板缺失 伴随着泪小管间隙的闭塞和膜表面的异常“屈曲”， 树突在另一种骨软化症模型中没有观察到这些骨细胞异常， 维生素D受体敲除，也不能DMP 1无效表型被高钙，磷酸盐， 饮食表明缺陷不是系统性的。根据这些观察，以下假设 已经提出：DMP 1对于成骨细胞/前骨细胞向骨细胞的转变，对于骨形成， 和维持腔隙-小管系统，以及调节骨细胞介导的对 机械负载为了解决这一假设，提出了三个具体目标：1）确定作用 DMP 1在成骨细胞向骨细胞转化及骨陷窝小管形成和维持中的作用 系统，2）确定加载和卸载对Dmp 1空骨架的影响，以及3）确定 DMP 1在成熟骨细胞功能及负荷反应中的作用。DMP 1的可用性- 裸小鼠和新开发的研究骨细胞形态和功能的技术提供了 研究人员发现，一种强有力的方法可以剖析出DMP 1在骨细胞功能中的特定作用， 在体外和体内对载荷的机械响应。这些研究可能会突出新的途径， 骨细胞中的机械刺激，可用于治疗代谢性骨疾病。

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.