BAG-75: UNIQUE MARKER OF PRIMARY BONE FORMATION

描述（由申请人提供）：初级骨在形态学上定义为 由软的间质组织直接形成的骨，没有钙化的软骨 或矿化前体阶段。长骨在出生后发育， 初级骨在初级软骨残余上的附着 海绵体，而额叶，顶叶，枕叶，颞叶， 颅面系统的上颌骨和下颌骨形成并保持为 原始骨在过去，对初级骨的研究较少受到重视 以及原发性和非原发性之间细胞和生化差异的真实程度， 板层骨未知。虽然板层骨代表成熟的结构， 初级骨是能够重新形成的板层骨的前体。 初级骨可以根据以下方面与板层（皮质）骨区分开来： 其沉积速度越快，精致的空间图案， 矿化，其在酸性磷蛋白中的表观特异性富集 BAG-75，其对所施加的生物力学力的敏感性增加， 全身激素我们建议BAG-75，通过其强烈的倾向， 自缔合成超分子微纤维复合物，作为 结构框架，其限定随后要钙化的初级骨基质的体积。本提案的目的是解决假设 BAG-75（骨酸性糖蛋白-75）是一种独特的基因产物， 表达仅限于活性新生钙化反应， 含有超过40个酪蛋白激酶磷酸化位点，一个或多个 聚谷氨酸钙结合基序，N-和O-连接寡糖 附着点，以及重复的模块化主要结构， 形成和矿化所需的杂聚合物协会 原始骨该项目符合R2 1机制的两个主要目标： 支持与主要研究相关的创新和高风险研究 NIDCR的使命领域，以及初步开发一系列研究， 这是未来重要研究的基础。例如，如果BAG-75 框架起着关键的组织作用，BAG-75的表面涂层可以 提高牙科和矫形植入物的稳定性; 8%-9%的1 美国每年有37，000例髋关节植入物需要在5-10分钟内进行翻修手术。 年我们设想BAG-75涂层非骨水泥植入物将 与宿主来源的BAG-75自结合，形成无缝的天然框架 导致其他基质成分的沉积和矿化 植入物表面的亚微米距离--提高 植入物.由于原生骨能够重新形成，未来 BAG-75启动子结构的确定可以形成一种新的 基因治疗方法，以逆转骨小梁连接的损失， 通过靶向局部刺激剂来调节牙槽骨体积与衰老的关系， 表达BAG-75的原代骨骨祖细胞，从而增强骨 体积和恢复失去的小梁连接。同位刺激 板层骨的形成预期不会具有相同的效果。这些 未来的功能研究需要确定BAG-75 cDNA序列。

DESCRIPTION (provided by applicant): Primary bone is defined morphologically as bone formed directly from soft mesenchymal tissue without a calcified cartilage or mineralized precursor stage. Long bones develop postnatally by the apposition of primary bone upon cartilaginous remnants in the primary spongiosa, while all or parts of the frontal, parietal, occipital, temporal, maxilla, and mandible bones of the craniofacial system form and remain as primary bone. Research on primary bone has received less emphasis in the past and the true extent of cellular and biochemical differences between primary and lamellar bone are unknown. While lamellar bone represents the mature structure, primary bone is the precursor of lamellar bone-capable of being formed de novo. Primary bone can be distinguished from lamellar (cortical) bone on the basis of the faster speed of its deposition, exquisite spatial patterning and mineralization, its apparent specific enrichment in acidic phosphoprotein BAG-75, and its increased sensitivity to applied biomechanical forces and systemic hormones. We propose that BAG-75, through its strong propensity to self-associate into supramolecular microfibrillar complexes, serves as a structural framework defining the volume of primary bone matrix to be subsequently calcified. The goal of this proposal is to address the hypothesis that BAG-75 (bone acidic glycoprotein-75) is a unique gene product whose expression is restricted to active de novo calcification reactions, and, which contains more than 40 casein kinase phosphorylation sites, one or more polyglutamic acid calcium-binding motifs, N- and O-linked oligosaccharide attachment sites, and a repetitive modular primary structure facilitating home-and heteropolymeric associations required for formation and mineralization of primary bone. This project fits two main objectives of the R2 1 mechanism: to support innovative and high-risk research relevant to the primary research mission areas of NIDCR, and, initial development of a line of research upon which significant future studies can be based. For example, if a BAG-75 framework serves a key organizational role, a surface coating of BAG-75 could improve the stability of dental and orthopedic implants; 8-9 percent of the 1 37,000 hip implants in the U.S. each year require revision surgery within 5-10 years. We envision that a BAG-75 coated, non-cemented implant would self-associate with host-derived BAG-75 to form a seamless natural framework leading to deposition of other matrix components and mineralization within submicron distances of the implant surface--improving functional longevity of implants. Since primary bone is capable of being formed de novo, future determination of the BAG-75 promoter structure could form the basis of a new gene therapy approach to reverse losses in trabecular bone connectivity and alveolar bone volume with aging by targeting local stimulatory agents to primary bone osteoprogenitor cells expressing BAG-75, thus enhancing bone volume and restoring lost trabecular connectivity. Stimulation of appositional formation by lamellar bone would not be expected to have the same effect. These future functional studies require determination of the BAG-75 cDNA sequence.