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CELLULAR BASIS OF CRANIOFACIAL BONE DISORDERS

颅面骨疾病的细胞基础

基本信息

批准号：
6523818
负责人：
Philip A Osdoby
金额：
$ 22.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-30 至 2004-07-31
项目状态：
已结题

项目摘要

Normal bone development and remodeling require complex humoral, cell- cell, and cell-matrix interactions. The integration of humoral and local signals is necessary to permit proper development, maintain mineral homeostasis, insure mechanical strength, and support haematopoeisis. There is now good evidence that osteoblasts can orchestrate osteoclast development and modulate osteoclast activity via paracrine signals. Information is just beginning to emerge that osteoclasts themselves synthesize and release factors that may influence bone remodeling. We therefore hypothesize that osteoclast-derived signals may function as autocrine effectors of osteoclast development and activity and therefore influence normal and pathological osteoclastogenesis and osteoclast-mediated bone resorption. We have shown that osteoclasts produce small proinflammatory molecules known as chemokines, such as IL-8 and GRO alpha and that such molecules can act to modulate osteoclast precursor recruitment, development, and activity. Therefore, to further investigate and define osteoclast autocrine regulation we propose the following specific aims: 1) Identify a profile of chemokines produced by human and mouse OC and determine which exhibit autocrine effects on OC function (bone resorption, motility, free radical production, TRAP, cathepsin K, and carbonic anhydrase II expression). The regulation of this subset of chemokines by select known modulators of OC function will be analyzed. Included here will be studies employing selective chemokine and chemokine receptor antagonists, chemokine neutralizing antibodies, and mouse OC-like cells formed in vitro from bone marrow obtained from IL-8 receptor knockout mice. 2) Identify and characterize the profile of chemokine receptors expressed on OC as a function of OC physiology, and pathophysiology. As part of this aim we will begin to elucidate the intracellular signal transduction pathways involved in chemokine modulation of OC activity. 3) Examine the potential role of chemokines in OC precursor recruitment and differentiation in vitro, in vivo, and in ovo. 4. Examine spatial and temporal aspects of chemokine and chemokine receptor expression in normal and pathological bone tissue by in situ hybridization and immunohistochemistry. Included here are mouse IL-8 receptor knockout studies. All of the above studies will use a combination of in vivo and in vitro approaches, and model systems including the mouse calvarial injection model for histomorphometric studies, human tissue sections for in situ hybridization and immunohistochemical analysis, isolated human and avian Ocs, human Oc-like cells, the mouse Oc-like cell developmental model, and cells obtained from an IL-8 receptor knockout mouse. Oc- chemokine production, mRNA steady state levels and regulation will be assessed by RT-PCP, RNAse protection assay, chemokine ELISA, and in situ hybridization techniques. Osteoclast development and activity will be evaluated based on functional, biochemical and molecular markers of the osteoclast phenotype, including bone resorption, osteoclast antigen expression tartarate-resistant acid phosphatase activity, and calcitonin receptor levels. Such studies are anticipated to reveal new aspects of normal bone remodeling mechanisms such as tooth eruption and have potential to lend insight into skeletal pathologies such as periodontal disease, implant loosening, osteoarthritis, other inflammatory skeletal disorders, and osteoporosis.

正常的骨骼发育和重塑需要复杂的体液，细胞- 细胞和细胞-基质相互作用。体液免疫和本地信号是必要的，以允许适当的发展，维护矿物质平衡，确保机械强度和支持造血现在有充分的证据表明，成骨细胞可以协调破骨细胞发育并通过以下途径调节破骨细胞活性旁分泌信号有消息称破骨细胞自身合成并释放因子，骨重建因此，我们假设破骨细胞源性信号可能作为破骨细胞发育的自分泌效应物起作用和活动，从而影响正常和病理破骨细胞生成和破骨细胞介导的骨吸收。我们有破骨细胞产生小的促炎分子，趋化因子，如IL-8和GRO α，这些分子可以作用于调节破骨细胞前体的募集、发育和活性。因此，为了进一步研究破骨细胞自分泌我们提出以下具体目标：1）确定一个轮廓人类和小鼠OC产生的趋化因子，并确定哪些表现出自分泌对OC功能的影响（骨吸收、运动、游离自由基产生、TRAP、组织蛋白酶K和碳酸酐酶II 表达式）。选择性趋化因子对这类趋化因子的调节将分析已知的OC功能调节剂。这里将包括使用选择性趋化因子和趋化因子受体的研究拮抗剂、趋化因子中和抗体和小鼠OC样细胞从IL-8受体敲除获得的骨髓体外形成小鼠 2)识别和表征趋化因子受体的概况在OC上表达作为OC生理学和病理生理学的函数。作为这一目标的一部分，我们将开始阐明细胞内信号参与OC活性的趋化因子调节的转导途径。 3)研究趋化因子在OC前体募集中的潜在作用以及体外、体内和卵内的分化。4.检查空间趋化因子和趋化因子受体表达的时间方面，原位杂交检测正常和病理骨组织，免疫组化包括小鼠IL-8受体敲除问题研究所有上述研究都将使用体内和体外的组合。体外方法和模型系统，包括小鼠颅骨用于组织形态计量学研究的注射模型，原位杂交和免疫组织化学分析，分离的人以及禽类OCs、人类OCs样细胞、小鼠OCs样细胞发育模型和从IL-8受体敲除小鼠获得的细胞。奥... 趋化因子的产生，mRNA的稳态水平和调节将是通过RT-PCP、RNA酶保护试验、趋化因子ELISA和原位杂交技术破骨细胞的发育和活性将是基于功能、生物化学和分子标记进行评估，破骨细胞表型，包括骨吸收、破骨细胞抗原抗酒石酸酸性磷酸酶活性和降钙素的表达受体水平这些研究预计将揭示新的方面，正常的骨重建机制，如牙齿萌出，有可能深入了解骨骼病理学，如牙周病疾病、植入物松动、骨关节炎、其他炎症性骨骼疾病和骨质疏松症。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An in vivo model system for the study of avian osteoclast recruitment and activity.

用于研究禽类破骨细胞募集和活性的体内模型系统。

DOI：
10.1016/0169-6009(90)90053-i
发表时间：
1990
期刊：
Bone and mineral
影响因子：
0
作者：
Webber,DM;Menton,D;Osdoby,P
通讯作者：
Osdoby,P

Osteoclast development in marrow cultured in calvaria-conditioned media.

在颅盖条件培养基中培养的骨髓中破骨细胞的发育。

DOI：
10.1016/0012-1606(88)90198-4
发表时间：
1988
期刊：
Developmental biology
影响因子：
2.7
作者：
Oursler,MJ;Osdoby,P
通讯作者：
Osdoby,P

Osteoclast 121F antigen expression during osteoblast conditioned medium induction of osteoclast-like cells in vitro: relationship to calcitonin responsiveness, tartrate resistant acid phosphatase levels, and bone resorptive activity.

破骨细胞121F抗原表达在成骨细胞条件培养基体外诱导破骨细胞样细胞过程中：与降钙素反应性、抗酒石酸酸性磷酸酶水平和骨吸收活性的关系。

DOI：
10.1002/jbmr.5650100109
发表时间：
1995
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
0
作者：
Collin-Osdoby,P;Oursler,MJ;Rothe,L;Webber,D;Anderson,F;Osdoby,P
通讯作者：
Osdoby,P

SDF-1 Increases Recruitment of Osteoclast Precursors by Upregulation of Matrix Metalloproteinase-9 Activity