Mechanisms of Rankl Mediated Osteoclast Activation

Rankl 介导的破骨细胞激活机制

• 批准号: 7812306
• 负责人: Steven L Teitelbaum
• 金额: $ 43.87万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812306
• 关键词: Autophagocytosis; Autophagosome; Bone Matrix; Bone Resorption; Bone Resorption Inhibition; Cell membrane; Cells; Confined Spaces; Crohn' s disease; Cytoskeleton; Disease; Failure; Intestines; Lysosomes; Mediating; Minerals; Mus; Organelles; Osteoclasts; Osteogenesis; Paneth Cells; Pathway interactions; Patients; Phase; Proteins; Secretory Vesicles; Signal Transduction; Structure; Surface; Vacuole; Vesicle; bone; cathepsin K; prevent; public health relevance; skeletal; synaptotagmin VII; therapeutic target; vacuolar H+-ATPase

DESCRIPTION (provided by applicant): Upon contact with bone, matrix-derived signals in the RANKL-induced osteoclast (OC) prompt the cell to polarize its cytoskeleton, eventuating in formation of an isolated microenvironment between the polykaryon and skeletal surface. Ultimate degradation of mineralized matrix is mediated by the ruffled border, an OC-unique structure which is the cell's resorptive organelle, contained within this confined space. Thus, the intracellular molecules mediating ruffled border formation and the bone-degrading products they deliver into the resorptive microenvironment are current or potential therapeutic targets. The ruffled border is formed by insertion of lysosome-derived vacuoles into the bone- apposed plasma membrane which we have established occurs under the aegis of synaptotagmin VII (Syt VII). These vesicles contain the vacuolar H+ATPase and cathepsin K which mobilize the mineral and organic phases of bone, respectively. Failure to deliver secretory vesicles to the bone-apposed plasmalemma arrests resorption. Autophagy is a conserved pathway by which proteins and organelles are sequested into autophagosomes and degraded. Like the ruffled border, autophagosomes fuse with lysosomes. Thus, a theoretical commonality exits between the mechanisms of bone resorption and autophagy. In this regard, we find that like SytVII deficiency, absence of the autophagy protein, Atg5, dampens bone degradation by preventing transport of cathepsin K into the resorptive microenvironment. This observation mirrors the failure of vesicle polarization in murine, Atg5-deficient intestinal Paneth cells and those of patients with Crohn's disease. We therefore hypothesize that the autophagy protein, Atg5, mediates RANKL-induced bone resorption by inhibiting secretory vesicle polarization. Thus, our supplemental specific aim is to determine the mechanism by which the autophagy protein, Atg5, mediates RANKL-induced bone resorption. PUBLIC HEALTH RELEVANCE: Inhibition of bone resorption remains our major venue for treating osteoporotic diseases. Information garnered from the supplemental Specific Aim may add to our armamentarium of potential anti-bone resorption therapeutic targets.

描述（由申请人提供）：与骨骼接触后，在RANKL诱导的破骨细胞（OC）中接触基质衍生的信号促使细胞偏振其细胞骨架，并在多骨和骨骼表面之间形成孤立的微环境。矿化基质的最终降解是由荷叶边的边界介导的，荷叶边的边界是一个OC-唯一的结构，是该细胞的吸收性细胞器，包含在此狭窄空间中。因此，细胞内分子介导荷叶边的边界形成以及它们输送到吸收性微环境中的骨骼降解产物是当前或潜在的治疗靶标。荷叶边的边界是通过将溶酶体衍生的液泡插入到骨所具有的质膜中形成的，我们已经在突触神经素VII（SYT VII）的宙斯盾下建立了。这些囊泡包含液泡H+ATPase和组织蛋白酶K，分别动员骨的矿物和有机相。未能将分泌囊泡传递到骨粘附的浆膜阻滞吸收。自噬是一种保守的途径，蛋白质和细胞器被隔离为自噬体并降解。像荷叶边的边界一样，自噬体与溶酶体融合。因此，骨吸收机制和自噬的机理之间的理论共同性。在这方面，我们发现像Sytvii缺乏症一样，缺乏自噬蛋白，ATG5，通过防止组织蛋白酶K运输到吸收性微环境中，会抑制骨骼降解。该观察结果反映了囊泡极化在鼠，ATG5缺陷肠细胞和克罗恩病患者的失败。因此，我们假设自噬蛋白ATG5通过抑制分泌囊泡极化来介导RANKL诱导的骨吸收。因此，我们的补充特定目的是确定自噬蛋白ATG5介导RANKL诱导的骨吸收的机制。 公共卫生相关性：抑制骨吸收仍然是我们治疗骨质疏松疾病的主要场所。从补充特定目标中获得的信息可能会增加我们潜在的抗骨吸收治疗靶标的武术。