RANK/NF-KappaB signaling in chondrogenesis

软骨形成中的 RANK/NF-KappaB 信号传导

• 批准号: 6561558
• 负责人: Brendan F Boyce
• 金额: $ 7.88万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-23 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561558
• 关键词: biological signal transduction; bone development; bone morphogenetic proteins; cartilage development; chondrocytes; developmental genetics; dwarfism; flow cytometry; gel mobility shift assay; gene expression; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; nuclear factor kappa beta; osteoprotegerin; pathologic process; polymerase chain reaction; receptor binding; regulatory gene; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Most of the skeleton forms by endochondral ossification in a highly regulated process in which skeletal elements are first laid down during embryogenesis in a cartilaginous framework. These cartilage elements are invaded by blood vessels and partly replaced by bone, laid down by bone forming osteoblasts and remodeled by bone destroying osteoclasts at epiphyseal growth plates, which form near the ends of the growing bones and control skeletal growth. Many genes have been identified during the past decade as regulators of this process, and mutation or deletion of them can result in various chondrodysplasias, including dwarfism. RANKL/RANK/NF- B signaling was shown to regulate osteoclastogenesis after deletion of these genes in mice led to osteopetrosis due to failure of osteoclast formation. Surprisingly, these knockout mice also have short limbs, but the role of this signaling pathway in endochondral ossification has not been studied in detail. In this proposal, we plan to obtain preliminary data that will provide definitive evidence of a role for this pathway in chondrogenesis and to develop an assay that will permit in vitro morphologic assessment of manipulation of this and other signaling pathways. Our Specific Aims are: 1) To determine the role of RANKL/RANK/NF- B signaling in chondrogenesis; 2) To determine the effects of absent RANK/NF- B signaling on chondrocyte gene expression. NF- B transcription factors regulate the expression of a variety of genes involved in numerous cell processes, including the early stages of limb development. Delineation of a specific role for these factors in endochondral ossification should open up a new field of investigation into the pathogenesis of the many forms of chondrodysplasia that to date do not yet have an identified molecular basis.

描述（由申请人提供）： 大多数骨骼在高度调节的过程中由内侧软骨骨化形成，在软骨框架中，在胚胎发生过程中首先放置骨骼元素。这些软骨元素被血管入侵，部分被骨骼代替，骨骼形成成骨细胞，并通过骨骼破坏的骨骼破坏骨的生长板的骨骼破坏，这些破骨细胞在生长骨骼的末端附近形成，并形成。在过去的十年中，许多基因已被确定为该过程的调节因子，并且它们的突变或缺失可能导致各种软骨浮肿，包括矮人。 RANKL/RANK/NF-B信号传导显示这些基因在小鼠中缺失后调节破骨细胞生成，导致骨质骨化导致骨质骨的骨质骨骼病。令人惊讶的是，这些敲除小鼠的四肢也短，但是该信号通路在内侧软骨骨化中的作用尚未详细研究。在此提案中，我们计划获得初步数据，这些数据将为该途径在软骨生成中的作用提供明确的证据，并开发一种将允许对这种和其他信号通路操纵的体外形态学评估的测定。我们的具体目的是：1）确定RANK/RANK/NF-B信号在软骨发生中的作用； 2）确定缺乏秩/nF-b信号传导对软骨细胞基因表达的影响。 NF-B转录因子调节涉及多种细胞过程的各种基因的表达，包括肢体发育的早期阶段。这些因素在内侧软骨骨化中的特定作用的描述应为迄今为止尚未确定的分子基础的多种形式的软骨增生性的发病机理打开新的研究领域。