Mechanisms of IKK Regulation of Basal and Inflammatory Osteoclastogenesis

IKK 调节基础和炎症破骨细胞生成的机制

• 批准号: 7793408
• 负责人: YOUSEF ABU-AMER
• 金额: $ 33.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-07 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7793408
• 关键词: Arthritis; Attenuated; Binding; Cell Nucleus; Chimera organism; Complement; Complementary DNA; Complex; Conflict (Psychology); Defect; Disease; Dominant-Negative Mutation; Event; Failure; Family; Gene Deletion; Genes; Germ Lines; IKK alpha; ITGAM gene; In Vitro; Individual; Inflammation Mediators; Inflammatory; Inflammatory Response; Knockout Mice; Lead; Mediating; Modeling; Molecular; Mus; Mutate; Null Lymphocytes; Osteoclasts; Osteolysis; Osteolytic; Pathway interactions; Phosphorylation; Phosphotransferases; Protein-Serine-Threonine Kinases; Proteins; Regulation; Relative (related person); Rheumatoid Arthritis; Role; Signal Transduction; Stimulus; TNF gene; TNFRSF5 gene; TNFSF11 gene; Tertiary Protein Structure; Time; Tissues; Transcription Initiation; Tyrosine; Tyrosine Phosphorylation; base; bone; cytokine; design; gain of function; in vivo; inhibitor/antagonist; molecular domain; novel; osteoclastogenesis; p65; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): The transcription factor NF-(B is essential for osteoclastogenesis and is considered a key modulator of inflammatory responses. Activation of NF-(B entails induction of a large I(B kinase (IKK) complex that comprises IKK1, IKK2, and IKK(/NEMO. IKK2 and IKK1 activate the canonical (p50/p65) and non- canonical (p52/relB) NF-(B pathways, respectively. Recent studies implicate IKK2 and IKK1 as essential for osteoclastogenesis, yet the mechanisms underling this function, remain unclear. In addition, IKK2 is considered as a key mediator of inflammatory events induced by TNF, LPS, and other pro-inflammatory agents (through the classical NF-(B pathway), whereas less is known about the role of IKK1 is such responses. In the past few years we have investigated molecular pathways regulating osteoclast activity in osteolytic responses, such as inflammatory osteolysis and arthritic bone erosion, and unveiled critical regulatory steps modulating NF-(B activation in osteoclast precursors. In this regard, we find that disruption of NF-(B activation at multiple levels attenuates osteoclastogenesis and inflammatory bone erosion. Specifically, we have shown that administration of dominant-negative forms of I(B(, that resist phosphorylation by IKK2; and most recently inhibition of IKK assembly with NEMO, using a decoy NEMO binding domain (NBD) peptide, all are successful approaches to inhibit osteoclastogenesis and bone erosion, in vitro and in vivo. Most importantly, we have preliminary evidence that, 1) failure of RANKL-induced osteoclastogenesis by IKK1-null OCPs is rescued by re-introduction of IKK1 cDNA constructs, and that 2) tissue-specific deletion of IKK2 in OCPs (using CD11b-cre) results with skeletally deformed mice. It is evident that osteoclastogenesis is impaired in the absence of IKK1 or IKK2, however, the precise mechanism(s) underlying signaling of IKKs in basal and inflammatory osteoclastogenesis remain scarce. Moreover, the relative contribution of either protein to these responses is indefinite. It is also known that IKK1 and IKK2 share considerable sequence and domain similarities, albeit they maintain distinct and non-overlapping functions. Thus, we hypothesize that IKK1 and IKK2 differentially regulate basal and inflammatory osteoclastogenesis through the alternative and classical NF-(B activation pathways. Hence, clarifying the individual roles of IKKs in osteoclastogenesis by investigating the details of their molecular signaling in osteoclasts, utilizing germ-line and specific tissue deletions of the relevant genes, will enable us to design strategies and selective inhibitors directed against IKK1 and IKK2 that may be useful for regulating osteoclastogenesis and alleviating inflammatory osteolysis in various bone resorptive disorders. Thus, we propose to investigate the following specific aims: 1) Determine the molecular role of IKK1 and IKK2 in basal and inflammatory osteoclastogenesis. 2) Determine the mechanism by which tyrosine phosphorylation regulates the fate and activity of IKK2 in the osteoclast lineage and it's impact on osteoclastogenesis. 3) Determine the role of IKK1 and IKK2 in inflammatory osteolysis, in vivo. PUBLIC HEALTH RELEVANCE: The transcription factor NF-(B is essential for osteoclastogenesis and modulates inflammatory responses. NF-(B is activated by the serine kinases, I(B kinase (IKK)-1, IKK-2, and IKK(/NEMO. Gene deletions of IKK1 or IKK2 led to defects in osteoclasts and inflammatory responses. Using IKK1 and IKK2-null mice, we propose to investigate the molecular domain contributions of IKK1 and IKK2 to osteoclastogenesis and inflammatory osteolysis, as is the case in inflammatory arthritis. Our proposal holds promise to identify novel selective anti-osteolytic therapies.

描述（由申请人提供）：转录因子NF-（B对于骨质质发生是必不可少的，被认为是炎症反应的关键调节因子。nF-的激活（B需要诱导一个大I（B激酶（IKK）复合体），该复合物是IKK1，IKK1，IKK2，IKK2，和IKK2，and ikkk（IKKK）（ikkk）（ikkk）（ikkk2，ikkk）（/nemo。和非规范（p52/relb）nf-（分别分别为B途径。最近的研究都暗示IKK2和IKK1对于骨质型构成是至关重要的，但是尚不清楚该功能的机制。此外，IKK2被认为是TNF，LPS和其他人（通过TNF）诱导的炎症事件的关键介体（通过LPS和其他疾病）（通过tnf）（通过tnf）的关键介体。在过去的几年中，我们对IKK1的作用的了解较少。多种水平的激活减弱了破骨细胞生成和炎症性骨侵蚀。侵蚀，体内和体内。在没有IKK1或IKK2的情况下，骨质发生受损，但是，IKK的基础和炎症性骨质质发生的确切机制仍然很少。因此，我们假设IKK1和IKK2通过替代和经典的NF-（B激活途径。相关的基因将使我们能够针对IKK1和IKK2设计策略和选择性抑制剂，这可能有助于调节骨构成型和减轻各种骨骼吸收性障碍的炎症性骨化的炎症性骨化。骨化核糖磷酸化的机制。并调节炎症反应。与炎症性关节炎一样，ikk1和ikk2 to骨化骨化和炎症性溶解度。