Mechanisms of RANKL Mediated Osteoclast Activation

RANKL 介导的破骨细胞激活机制

• 批准号: 7458381
• 负责人: Steven L Teitelbaum
• 金额: $ 49.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458381
• 关键词: Adaptor Signaling Protein; Bone Resorption; Cells; Complex; Complication; Cysteine-Rich Domain; Development; Engineering; Event; Funding; Goals; Implant; Inflammation; Inflammatory; Macrophage Colony-Stimulating Factor; Mediating; Monomeric GTP-Binding Proteins; Orthopedics; Osteoclasts; Osteolysis; Osteoporosis; Pharmaceutical Preparations; Positioning Attribute; Process; Public Health; Purpose; Recruitment Activity; Regulation; Resolution; Rheumatoid Arthritis; Signal Pathway; Signal Transduction; Structure; TNF gene; TRANCE protein; Therapeutic; Variant; base; bone; bone loss; cytokine; design; inhibitor/antagonist; insight; novel; osteoclastogenesis; paxillin; prevent; receptor

DESCRIPTION (provided by applicant): Inflammatory osteolysis, as occurs in rheumatoid arthritis and orthopedic implant loosening, reflects accelerated osteoclast (OC) recruitment and activation. Hence, discovering the means by which local inflammation recruits and activates OCs is central to preventing this crippling complication. Our overriding goal has been to detail the mechanisms by which cytokines, such as TNF, RANKL and M-CSF mediate bone loss. We have achieved the aims of our previous application by characterizing the contributions of various TNF target cells to the osteoclastogenic process and detailing many of the intracellular events by which TNF promotes osteoclastogenesis. In the present proposal we turn to the cytokine essential for all pathological bone resorption, namely RANKL, whose crystal structure, in complex with its receptor, RANK, we resolved in the current funding period. While RANKL is essential for OC differentiation, it also enhances the bone resorptive activity of the mature OC, a process we find depends upon the cytokine's regulation of the cytoskeletal adaptor protein, paxillin and the small GTPase, Rac. Furthermore, our resolution of the RANKL/RANK crystal structure and that of RANKL with the cysteine-rich domains of OPG, the decoy receptor, positions us to develop structure-based RANKL antagonists to arrest RANK signaling in the OC. Given that inhibition of the RANK signaling pathway has proven therapeutic benefit, these novel RANKL inhibitors may impact the treatment of pathological osteolysis. Thus, we hypothesize that: 1) RANKL activation of the OC is mediated via paxillin 2) RANKL activation of the OC is mediated via Rac and 3) Structure-based RANKL antagonists will arrest OC development and function. Our Specific Aims are therefore to 1) Determine the mechanisms by which paxillin mediates RANKL activation of the OC 2) Determine the mechanisms by which RANKL activates Rac in the OC and 3) Engineer variants of RANKL and OPG that disrupt RANK signaling in the OC. PUBLIC HEALTH RELEVANCE. Osteoclasts are the cells which destroy bone, and thus, their increased activity is responsible for most forms of pathological bone loss such as osteoporosis or that attending rheumatoid arthritis. The key molecule which activates ostoclasts is known as RANK ligand (RANKL). The purpose of this proposal is to gain insight into the mechanism by which RANKL activates osteoclasts and to design candidate drugs which will inhibit this event and consequently, prevent pathological bone loss.

描述（由申请方提供）：炎症性骨质溶解，如类风湿性关节炎和骨科植入物松动中发生的，反映了破骨细胞（OC）的加速募集和激活。因此，发现局部炎症招募和激活OC的方式是预防这种严重并发症的关键。我们的首要目标是详细说明细胞因子如TNF、RANKL和M-CSF介导骨丢失的机制。通过表征各种TNF靶细胞对破骨细胞生成过程的贡献并详细描述TNF促进破骨细胞生成的许多细胞内事件，我们已经实现了我们先前申请的目的。在本提案中，我们转向所有病理性骨吸收所必需的细胞因子，即RANKL，其晶体结构与其受体RANK复合，我们在当前资助期内解决了。虽然RANKL是OC分化所必需的，但它也增强了成熟OC的骨吸收活性，我们发现这一过程取决于细胞因子对细胞骨架衔接蛋白桩蛋白和小GT3蛋白Rac的调节。此外，我们对RANKL/RANK晶体结构的解析以及RANKL与OPG（诱饵受体）富含半胱氨酸结构域的解析，使我们能够开发基于结构的RANKL拮抗剂，以阻止OC中的RANK信号传导。鉴于RANK信号通路的抑制已证明具有治疗获益，这些新型RANKL抑制剂可能会影响病理性骨质溶解的治疗。因此，我们假设：1）OC的RANKL活化通过桩蛋白介导，2）OC的RANKL活化通过Rac介导，3）基于结构的RANKL拮抗剂将阻止OC的发育和功能。因此，我们的具体目的是：1）确定桩蛋白介导RANKL激活OC的机制; 2）确定RANKL激活OC中Rac的机制; 3）RANKL和OPG的工程变体，其破坏OC中的RANK信号传导。公共卫生相关性。破骨细胞是破坏骨骼的细胞，因此，它们的活性增加是导致大多数形式的病理性骨丢失的原因，例如骨质疏松症或类风湿性关节炎。激活破骨细胞的关键分子被称为RANK配体（RANKL）。该提案的目的是深入了解RANKL激活破骨细胞的机制，并设计抑制该事件的候选药物，从而预防病理性骨丢失。