Studies of the Fate of the Osteoclast

破骨细胞命运的研究

• 批准号: 8215871
• 负责人: Brendan F Boyce
• 金额: $ 33.04万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215871
• 关键词: Affect; Albers-Schonberg disease; Animal Disease Models; Arthritis; Bone Diseases; Bone Marrow; Bone Resorption; Cells; Complex; Cyclin D1; Data; Development; Disease; FOS gene; Health; Hematopoietic stem cells; In Vitro; Inflammation; Inflammatory; Joints; Knee joint; Knockout Mice; Lead; Mediating; Modeling; Mus; Osteitis; Osteoblasts; Osteoclasts; Pathologic; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Play; Postmenopausal Osteoporosis; Process; Proteins; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Synovitis; TNF gene; TNFSF11 gene; Testing; Transgenic Organisms; base; bone; bone cell; bone loss; cytokine; in vivo; loss of function; member; novel; novel therapeutic intervention; p65; prevent; response; transcription factor

DESCRIPTION (provided by applicant): Osteoclasts are essential for bone modeling and remodeling and mediate bone loss in common bone diseases, including rheumatoid arthritis and postmenopausal osteoporosis, in which levels of proinflammatory cytokines, such as TNF, are increased and drive osteoclast formation both directly and indirectly through RANKL and three sets of transcription factors: NF-?B; c-Fos; and NFATc1. Expression of these is essential for osteoclast formation. RANKL/RANK signals through a canonical NF-?B1/p65 and an alternative NF-?B2/RelB pathway. To-date, most studies of NF-?B in osteoclasts have focused on the canonical pathway, and much less is known about the functional roles of NF-?B2 and RelB in regulating osteoclasts and other bone cells. Recently, we found that TNF induces NF-?B2 expression and that deletion of NF-?B2 increases TNF-induced osteoclast formation. TNF transgenic/NF-?B2-/- mice develop earlier and more severe joint erosion and inflammation and systemic bone loss than TNF-Tg mice. Furthermore, we found that RelB null mice have mild osteopetrosis. These findings highlight the importance of the alternative pathway in bone and suggest a new role for TNF to limit RANKL-induced bone loss in addition to its known role to stimulate osteoclast formation. Based on our preliminary data, we hypothesize that TNF can induce NF-?B2 expression to limit osteoclast formation stimulated by RANKL and that manipulation of NF-?B2/RelB expression will directly affect osteoclast functions. This hypothesis will be tested in the following 3 Specific Aims. In Aim 1, we will determine if NF-?B2 limits OC formation by controlling signaling in both the canonical and alternative NF-?B pathways. In Aim 2, we will determine the roles of NF-?B2 and RelB in osteoclast formation and activity. In Aim 3, we will determine the effects of over-expression of NF-?B2p100 on TNF-induced bone loss. Our proposed studies should define the roles of NF-?B2 and RelB in osteoclast formation and activity and provide proof of concept that they are strong candidates for novel therapeutic intervention to limit cytokine-stimulated bone loss. PUBLIC HEALTH RELEVANCE Osteoclasts are the cells that degrade bone and over-activity of them causes bone loss in common diseases, such as rheumatoid arthritis. Our proposed studies, using animal models of these diseases, should lead to a better understanding of how osteoclast activity is regulated and eventually to the development of a novel therapy to limit this activity in these bone disorders.

描述（由申请人提供）：破骨细胞对于骨建模和重塑和介导常见骨疾病的骨质流失至关重要，包括类风湿关节炎和绝经后骨质疏松症，其中促炎细胞因子的水平，例如TNF，例如TNF，如TNF，以及直接通过分裂和驱动Osteoclast形式的迁移和驱动器分组。 nf-？b; c-fos;和NFATC1。这些表达对于破骨细胞形成至关重要。通过规范的NF-？B1/P65和替代NF-？B2/RERB途径的RANKL/等级信号。迄今为止，大多数NF-？B在破骨细胞中的研究都集中在规范的途径上，而对NF-？B2和RELB在调节破骨细胞和其他骨细胞中的功能作用知之甚少。最近，我们发现TNF诱导NF-？B2的表达，而NF-？B2的缺失会增加TNF诱导的破骨细胞的形成。与TNF-TG小鼠相比，TNF转基因/NF-？B2 - / - 小鼠早于更早，更严重的关节侵蚀和更严重的关节侵蚀，炎症和全身性骨丢失。此外，我们发现RELB无效小鼠患有轻度骨质术。这些发现突出了骨骼中替代途径的重要性，并提出了TNF限制RANKL诱导的骨质流失的新作用，除了其已知的作用以刺激破骨细胞形成。基于我们的初步数据，我们假设TNF可以诱导NF-？B2表达以限制RANKL刺激的破骨细胞形成，并且对NF-？B2/RELB表达的操纵将直接影响骨细胞功能。该假设将在以下三个特定目标中进行检验。在AIM 1中，我们将通过控制规范和替代NF-途径中的信号来确定NF-？B2限制OC的形成。在AIM 2中，我们将确定NF-？B2和RELB在破骨细胞形成和活性中的作用。在AIM 3中，我们将确定NF-？B2P100过度表达对TNF诱导的骨质流失的影响。我们提出的研究应定义NF-？B2和RELB在破骨细胞形成和活动中的作用，并提供概念证明，即它们是新型治疗干预措施的强大候选者，以限制细胞因子刺激的骨质流失。公共卫生相关性破骨细胞是降解骨骼的细胞，其过度活跃会导致普通疾病（例如类风湿关节炎）的骨质流失。我们提出的研究使用这些疾病的动物模型，应更好地了解破骨细胞活性的调节，并最终导致新的疗法的发展，以限制这些骨骼疾病中的这种活性。