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)： 大多数骨骼是通过软骨内骨化形成的，这是一个高度调控的过程，在这个过程中，骨骼元素首先在软骨框架内的胚胎发生期间放置。这些软骨元素被血管侵入，部分被骨取代，由成骨细胞铺设，并由骨痂生长板上的破骨细胞重塑，这些破骨细胞在生长骨的末端附近形成，控制骨骼的生长。在过去的十年中，许多基因被确定为这一过程的调节基因，它们的突变或缺失可以导致各种软骨发育不良，包括侏儒症。RANKL/RANK/NF-B信号被证明在这些基因缺失导致破骨细胞形成失败导致小鼠骨化后调节破骨细胞的形成。令人惊讶的是，这些基因敲除的小鼠也有短肢，但这一信号通路在软骨内成骨中的作用尚未得到详细研究。在这项提案中，我们计划获得初步数据，为这一途径在软骨形成中的作用提供明确的证据，并开发一种分析方法，允许在体外对这一途径和其他信号途径的操纵进行形态评估。我们的具体目标是：1)确定RANKL/RANK/NF-B信号在软骨形成中的作用；2)确定RANK/NF-B信号缺失对软骨细胞基因表达的影响。核因子-B转录因子调节多种基因的表达，这些基因参与许多细胞过程，包括肢体发育的早期阶段。阐明这些因子在软骨内骨化中的特定作用，将为许多软骨发育不良的发病机制开辟一个新的领域，到目前为止，这些软骨发育不良的分子基础尚不明确。