CARBOHYDRATE RECEPTORS IN OSTEOCLAST FUNCTION
破骨细胞功能中的碳水化合物受体
基本信息
- 批准号:2132375
- 负责人:
- 金额:$ 4.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-09-30 至 1996-09-29
- 项目状态:已结题
- 来源:
- 关键词:antibody biological models biological signal transduction bone density carbohydrate receptor carbohydrate structure cell cell interaction exo alpha sialidase extracellular matrix glycoproteins laboratory rat lectin oligosaccharides osteoblasts osteoclasts osteoporosis physiologic bone resorption receptor binding receptor expression
项目摘要
In bone, osteoblast/osteoclast interactions appear to be mediated
indirectly in part by components of the extracellular matrix. To
control formation, induction, localization, and activation of
osteoclasts, osteoblasts may transfer signals/messages via
macromolecules they secrete and deposit in the extracellular matrix or
osteoid. Non-collagenous glycoproteins, ie., osteopontin, bone
sialoprotein, bone acidic glycoprotein-75, decorin, and biglycan,
synthesized by osteoblasts and secreted into forming bone matrix
contain 0-linked and/or N-linked oligosaccharide chains. However, the
significance of these post-translational modifications to the
development and function of osteoclasts has not been fully explored.
Our hypothesis is that carbohydrate receptors (lectins or carbohydrate
recognition domains) play a role in the development and function of
osteoclasts. We will address the following basic question. AIM 1. Do
multinucleated osteoclasts express carbohydrate receptors in vivo in
young rat bone and in the marrow ablation model of accelerated bone
turnover? The marrow ablation model permits an analysis of different
predominant stages of bone turnover, ie., osteoclast rich phase at 8-
10 days, and yields induced bone amenable to isolation of RNA or
sectioning. Considering a shared stem cell origin of osteoclasts with
macrophage/ monocyte cells, which express carbohydrate receptors used
in endocytosis or adhesion to matrices, and the availability of cloned
receptor cDNAs, our approach will be to first determine whether
osteoclasts co-express known macrophage/Kupffer cell lectins through
use of Northern blotting and in situ hybridization. Despite data from
the mid 1980's to the contrary, osteoclasts and macrophage-like cells
have been shown to share a number of common antigens and a wealth of
data on macrophage/Kupffer cell/leukocyte carbohydrate receptors has
appeared in the intervening period. However, if Northern blots with
induced bone are negative for these cloned lectins, a second approach
will be taken to demonstrate carbohydrate receptors in/on osteoclasts
in tissue sections through direct binding and competition with
carbohydrate ligands. These alternate approaches should lead to an
answer to the question posed in Aim 1.
Clinical Relevance: Skeletal and alveolar bone mass represents the net
sum of dynamic resorptive and formative processes which continue
throughout life in humans. All individuals experience osteopenia with
increasing age. When bone mass reaches a critical threshold, fractures
occur with little trauma (osteoporosis). Osteoporosis is a major
health problem in the U.S. where it is estimated that 20 million
people are currently affected and 1.3 million fractures are
attributable to it each year. While supported by limited research, the
scientific literature suggests that skeletal osteopenia may be
accompanied by accelerated loss of craniofacial bone; in recognition
of this fact, NlDR and NIAMSD have initiated a Research Program in
Oral Bone Loss and Osteoporosis. This proposal is a new investigation
of carbohydrate receptor expression by osteoclasts in young and
induced bone tissue. If present, carbohydrate receptors could mediate
the localization, attachment, fusion, and resorptive function of
osteoclasts on bone. Osteoclast-matrix recognition mechanisms are a
prime target for therapeutic intervention.
在骨骼中,成骨细胞/破骨细胞相互作用似乎是介导的
部分地间接通过细胞外基质的成分。到
控制形成、诱导、定位和激活
破骨细胞、成骨细胞可以通过以下途径传递信号/消息
它们分泌并沉积在细胞外基质中的大分子或
类骨质。非胶原糖蛋白,即骨桥蛋白、骨
唾液酸蛋白、骨酸性糖蛋白75、核心蛋白聚糖和双糖链蛋白聚糖,
由成骨细胞合成并分泌形成骨基质
含有0-连接和/或N-连接的寡糖链。然而,
这些翻译后修饰对
破骨细胞的发育和功能尚未得到充分探索。
我们的假设是碳水化合物受体(凝集素或碳水化合物
识别域)在发育和功能中发挥作用
破骨细胞。我们将解决以下基本问题。目标 1. 执行
多核破骨细胞在体内表达碳水化合物受体
幼鼠骨及加速骨骨髓消融模型
周转?骨髓消融模型允许分析不同的
骨转换的主要阶段,即 8 时的破骨细胞富集阶段
10天,产生适合分离RNA或的诱导骨
切片。考虑到破骨细胞与破骨细胞具有共同的干细胞起源
巨噬细胞/单核细胞,表达所使用的碳水化合物受体
内吞作用或基质粘附,以及克隆的可用性
受体 cDNA,我们的方法是首先确定是否
破骨细胞通过共表达已知的巨噬细胞/库普弗细胞凝集素
使用Northern印迹和原位杂交。尽管数据来自
20世纪80年代中期恰恰相反,破骨细胞和巨噬细胞样细胞
已被证明具有许多共同的抗原和丰富的
巨噬细胞/库普弗细胞/白细胞碳水化合物受体的数据
出现在其间的时期。然而,如果 Northern 印迹
诱导骨对这些克隆的凝集素呈阴性,这是第二种方法
将被用来证明破骨细胞内/上的碳水化合物受体
通过直接结合和竞争在组织切片中
碳水化合物配体。这些替代方法应该会导致
回答目标 1 中提出的问题。
临床相关性:骨骼和牙槽骨量代表净骨量
持续不断的动态再吸收和形成过程的总和
在人类的整个一生中。所有个体都会经历骨质减少
年龄增加。当骨量达到临界阈值时,就会发生骨折
发生时创伤很小(骨质疏松症)。骨质疏松症是一大
美国估计有 2000 万人面临健康问题
目前有 130 万人受到影响,有 130 万人骨折
每年都归功于它。尽管得到有限研究的支持,
科学文献表明骨骼骨质减少可能是
伴有颅面骨加速流失;认可
鉴于这一事实,NlDR 和 NIAMSD 启动了一项研究计划
口腔骨质流失和骨质疏松症。该提案是一项新的调查
青少年和青少年破骨细胞碳水化合物受体表达的影响
诱导骨组织。如果存在,碳水化合物受体可以介导
的定位、附着、融合和再吸收功能
骨头上的破骨细胞。破骨细胞基质识别机制是
治疗干预的主要目标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JEFFREY Paul GORSKI其他文献
JEFFREY Paul GORSKI的其他文献
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{{ truncateString('JEFFREY Paul GORSKI', 18)}}的其他基金
Eleventh International Conference on the Chemistry and Biology of Mineralized Tis
第十一届国际矿化钛化学与生物学会议
- 批准号:
8459213 - 财政年份:2013
- 资助金额:
$ 4.61万 - 项目类别:
BAG-75: UNIQUE MARKER OF PRIMARY BONE FORMATION
BAG-75:初级骨形成的独特标记
- 批准号:
6642816 - 财政年份:2002
- 资助金额:
$ 4.61万 - 项目类别:
BAG-75: UNIQUE MARKER OF PRIMARY BONE FORMATION
BAG-75:初级骨形成的独特标记
- 批准号:
6464697 - 财政年份:2002
- 资助金额:
$ 4.61万 - 项目类别:
IN VIVO/IN VITRO STUDIES OF BONE ACIDIC GLYCOPROTEIN-75
骨酸性糖蛋白-75 的体内/体外研究
- 批准号:
3437176 - 财政年份:1991
- 资助金额:
$ 4.61万 - 项目类别:
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