The Role of Bone Sialoprotein in Modulating Periodontal Development and Repair

项目摘要 在美国，47%的30岁或30岁以上的成年人受到牙周病的影响，而这一比例 在65岁或以上的成年人中，随着年龄的增长，这一比例增加到70%。牙周复合体，由牙槽骨组成， 牙骨质、牙龈和牙周膜(PDL)，以确保正确的牙齿附着和 滋养，分配咬合力，保持牙槽骨高度，保护牙周组织，防止 入侵的微生物。牙周病导致这些组织中的一个或多个被破坏，这 最终导致部分或全部无牙以及咀嚼复合体功能减退，自我修复 尊重，和人际关系。大多数疗法是不可预测的，而且在修复方面也不成功 三个组织都丢失或损坏了。骨涎蛋白(ibsp基因；bsp蛋白)是一种多功能的胞外蛋白。 在骨骼和牙列的矿化组织中发现的基质蛋白，包括牙槽骨和 牙骨质。完全基因敲除小鼠(IBSP-/-)表现为脱细胞牙骨质减少，牙槽骨矿化减少， 牙周膜脱离，严重的牙槽骨吸收，牙齿脱落和牙周破坏。到目前为止，几乎所有的 对BSP的研究主要集中在其在颅骨和颅后发育中的作用。然而，它的双重功能在 成骨细胞和破骨细胞也提示在骨重建的耦合过程中发挥重要作用； 小鼠在拔除磨牙后牙槽骨凹陷愈合过程中表现出明显的缺陷。虽然这一点很重要 BSP在牙周复合体中很明显，其分子功能尚不清楚。我们认为BSP是一个关键 牙周发育、动态平衡和修复中的分子。概述的实验将测试我们的中心 BSP通过其关键细胞功能调节牙周发育和修复的假说 牙周功能：成牙骨质细胞、成骨细胞和破骨细胞。这项建议的总体目标是： 1)从外胚间充质中有条件地切除IBSP以确定BSP和成牙骨质细胞谱系的起源 与上皮细胞群比较；2)阐明天门冬氨酸在成骨细胞和破骨细胞功能中的作用(S)(S) 通过有条件地去除来自成骨细胞和破骨细胞的IBSP来修复牙槽骨愈合；确定 BSP在绝经后骨质疏松对去卵巢(OVX)大鼠骨代谢影响中的作用 绝经后骨质疏松症模型。从这项提案中获得的知识有望为 牙周复合体的新的修复疗法的发展。圆满完成 拟议的研究将为了解天冬氨酸在牙周生物学中的作用(S)以及 以成骨细胞-破骨细胞过度脱钩为特征的疾病。

Project Summary In the United States, 47% of adults 30 years or older are affected by periodontal disease, and this rate increases with age to 70% in adults 65 years or older. The periodontal complex, consisting of alveolar bone, cementum, gingiva, and the periodontal ligament (PDL), works to ensure proper tooth attachment and nourishment, distribute occlusal forces, maintain alveolar bone height, and protect the periodontium from invading microbes. Periodontal disease leads to the destruction of one or more of these tissues, which ultimately results in partial or total edentulism as well as reduced function of the masticatory complex, self- esteem, and interpersonal relationships. Most therapies are unpredictable as well as unsuccessful at repairing all three lost or damaged tissues. Bone sialoprotein (Ibsp gene; BSP protein) is a multifunctional, extracellular matrix protein found in mineralized tissues of the skeleton and dentition, including alveolar bone and cementum. Total knockout mice (Ibsp-/-) display reduced acellular cementum, hypomineralized alveolar bone, PDL detachment, severe alveolar bone resorption, tooth loss, and periodontal destruction. To date, nearly all studies on BSP focus on its roles in cranial and postcranial development. However, its dual functions in osteoblasts and osteoclasts also suggest an important role in the coupled process of bone remodeling; Ibsp-/- mice show dramatic defects in alveolar bone socket healing following molar extraction. While the importance of BSP in the periodontal complex is evident, its molecular functions remain unclear. We propose BSP is a key molecule in periodontal development, homeostasis, and repair. The outlined experiments will test our central hypothesis that BSP modulates periodontal development and repair through its functions in key cells for periodontal function: cementoblasts, osteoblasts, and osteoclasts. The overall objectives of this proposal are: 1.) define the origin of BSP and cementoblast lineage using conditional ablation of Ibsp from ectomesenchymal vs. epithelial cell populations; 2.) elucidate the role(s) of BSP in osteoblast and osteoclast function(s) in alveolar bone healing by conditionally ablating Ibsp from osteoblasts and osteoclasts; and 3.) determine the role of BSP in postmenopausal osteoporotic changes to bone metabolism using an ovariectomy (OVX) rodent model of postmenopausal osteoporosis. The knowledge gained from this proposal holds promise for the development of novel and reparative therapies of the periodontal complex. Successful completion of the proposed research will provide key insights into the function(s) of BSP in periodontal biology as well as diseases characterized by excessive osteoblast-osteoclast decoupling.