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）：与骨接触后，RANKL 诱导的破骨细胞 (OC) 中的基质衍生信号促使细胞极化其细胞骨架，最终在多核体和骨骼表面之间形成隔离的微环境。矿化基质的最终降解是由褶皱边界介导的，这是一种 OC 独特的结构，是细胞的再吸收细胞器，包含在这个有限的空间内。因此，介导褶皱边界形成的细胞内分子和它们递送到再吸收微环境中的骨降解产物是当前或潜在的治疗靶点。褶皱边界是通过将溶酶体衍生的液泡插入骨贴合质膜而形成的，我们已经确定这是在突触结合蛋白 VII (Syt VII) 的支持下发生的。这些囊泡含有液泡 H+ATP 酶和组织蛋白酶 K，它们分别动员骨的矿物相和有机相。未能将分泌囊泡输送到骨附着的质膜会阻止吸收。自噬是一种保守的途径，蛋白质和细胞器通过该途径被隔离到自噬体中并被降解。就像褶边一样，自噬体与溶酶体融合。因此，骨吸收和自噬机制之间存在理论上的共性。在这方面，我们发现与 SytVII 缺陷一样，自噬蛋白 Atg5 的缺失可以通过阻止组织蛋白酶 K 转运至再吸收微环境来抑制骨降解。这一观察结果反映了小鼠 Atg5 缺陷型肠道潘氏细胞和克罗恩病患者的囊泡极化失败。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，我们的补充具体目标是确定自噬蛋白 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途径。从补充的具体目标中获得的信息可能会增加我们潜在的抗骨吸收治疗目标的武器库。