Studies of the Fate of the Osteoclast

描述（由申请人提供）：破骨细胞对于骨建模和重塑至关重要，并介导常见骨疾病（包括类风湿性关节炎和绝经后骨质疏松症）中的骨丢失，其中促炎细胞因子（如TNF）水平增加，并通过RANKL和三组转录因子（NF-？B; c-Fos;和NFATc 1。这些蛋白的表达对于破骨细胞的形成至关重要。RANKL/RANK信号通过一个典型的NF-？B1/p65和另一种NF-？B2/RelB途径。迄今为止，大多数NF-？破骨细胞中的B主要集中在经典途径，而对NF-？B2和RelB在调节破骨细胞和其他骨细胞中的作用。最近，我们发现，TNF诱导NF-？B2表达和NF-？B2增加TNF诱导的破骨细胞形成。TNF转基因/NF-？与TNF-Tg小鼠相比，B2-/-小鼠发生更早和更严重的关节侵蚀和炎症以及全身性骨丢失。此外，我们发现RelB基因敲除小鼠具有轻度的骨硬化症。这些发现强调了骨骼中替代途径的重要性，并表明TNF除了刺激破骨细胞形成的已知作用外，还具有限制RANKL诱导的骨丢失的新作用。根据我们的初步数据，我们假设，TNF可以诱导NF-？B2表达限制RANKL刺激破骨细胞形成和NF-？B2/RelB的表达将直接影响破骨细胞的功能。该假设将在以下3个特定目标中进行检验。在目标1，我们将确定如果NF-？B2通过控制典型和替代NF-？B途径。在目标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。在目标3中，我们将确定NF-？B2 p100对TNF诱导的骨丢失的影响我们建议的研究应该定义NF-？B2和RelB在破骨细胞形成和活性中的作用，并提供了概念证明，即它们是限制精氨酸刺激的骨丢失的新型治疗干预的强有力候选者。破骨细胞是降解骨骼的细胞，它们的过度活动会导致常见疾病（如类风湿性关节炎）中的骨质流失。我们提出的研究，使用这些疾病的动物模型，应导致更好地了解破骨细胞活性是如何调节的，并最终开发一种新的治疗方法，以限制这种活动在这些骨骼疾病。

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.