BAG-75: UNIQUE MARKER OF PRIMARY BONE FORMATION

描述(申请人提供)：初级骨骼在形态上定义为 骨直接由软间充质组织形成，没有钙化的软骨 或矿化前驱阶段。长骨是在出生后发育的 原发骨与软骨残留物的贴合 海绵状，而额部、顶部、枕部、颞部、 上颌骨和颅面系统的下颌骨形成并保持为 初级骨骼。在过去，对初级骨骼的研究受到的重视较少 以及原发和非原发的细胞和生化差异的真实程度 板层骨是未知的。而板层骨代表成熟的结构， 初级骨是板层骨的前身--能够从头形成。 初级骨与板层(皮质)骨可根据以下因素加以区分 更快的沉积速度，精致的空间图案和 矿化作用及其在酸性磷酸蛋白中的表观特异性富集性 Bag-75，以及它对所施加的生物机械力和 全身荷尔蒙。我们建议BAG-75，因为它有很强的 自缔合成超分子微纤维复合体，作为一种 定义后续钙化的初级骨基质体积的结构框架。这项提议的目标是解决这一假设 BAG-75(骨酸性糖蛋白-75)是一种独特的基因产物，其 表达仅限于活跃的从头钙化反应，并且， 包含40多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-连接的寡糖 附着点，和一个重复的模块化初级结构，便于回家和 形成和成矿所需的杂多缔合 初级骨骼。该项目符合R2 1机制的两个主要目标： 支持与初步研究相关的创新和高风险研究 NIDCR任务区，并初步制定了一系列关于 这些重要的未来研究可以作为基础。例如，如果一个袋子-75 框架起着关键的组织作用，袋子-75的表面涂层可以 提高牙科和矫形植入物的稳定性； 美国每年有3.7万例髋关节植入物需要在5-10年内进行翻修手术 好几年了。我们设想一种包-75涂层的非粘固性植入物将 与宿主衍生的BAG-75自我关联，形成无缝的自然框架 导致其他基质成分的沉积和矿化 种植体表面的亚微米距离--提高功能寿命 植入物。既然初级骨骼能够从头形成，未来 对BAG-75启动子结构的测定可以形成新的 基因治疗方法逆转骨小梁连通性和骨小梁缺失 局部刺激剂靶向治疗牙槽骨体积与增龄的关系 原代骨祖细胞表达BAG-75，从而增强骨骼 体积和恢复丢失的小梁连接。同位刺激 板层骨的形成不会有同样的效果。这些 未来的功能研究需要对BAG-75的cDNA序列进行测定。

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.