The role of autophagy in the osteoblast lineage cells

自噬在成骨细胞谱系细胞中的作用

• 批准号: 10491663
• 负责人: Melda Onal
• 金额: $ 23.99万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-16 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491663
• 关键词: Address; Age; Apoptosis; Autophagocytosis; Bone remodeling; Cell Death; Cell Differentiation process; Cell Lineage; Cells; Cellular Stress; Cessation of life; Collagen; Functional disorder; Mediating; Molecular Chaperones; Musculoskeletal Diseases; Osteoblasts; Osteocytes; Osteogenesis; Osteogenesis Imperfecta; Pathology; Pathway interactions; Play; Research; Role; Tissues; biological adaptation to stress; bone; bone loss; cell injury; cell type; endoplasmic reticulum stress; improved; in vivo; osteoblast differentiation; progenitor; skeletal; skeletal disorder; stressor

Cellular stressors are thought to cause dysfunction or death of osteoblast lineage cells (progenitors, bone-forming osteoblasts, and remodeling orchestrator osteocytes) and thereby cause bone loss in skeletal diseases. Autophagy is a cell stress-response pathway that recycles cellular components damaged by cellular stressors. There are three types of autophagy: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. These different types of autophagy differ in mechanism, target, and function. In addition to stress response, autophagy pathways also have cell-type-specific functions, such as controlling cell differentiation. We have previously shown that macroautophagy and CMA contribute to bone remodeling, albeit at different levels. Herein, we hypothesize that “Autophagy promotes the differentiation, survival, and function of osteoblast lineage cells”. In previous studies, we have shown that lack of macroautophagy resulted in decreased osteoblast numbers and bone formation. In Aim1, we will examine possible mechanisms by which lack of macroautophagy decreases osteoblast numbers and bone formation. Specifically, we will examine if lack of macroautophagy alters proliferation, apoptosis, or differentiation of osteoblast lineage cells. Our preliminary studies suggest that osteoblastic cells use CMA to protect from ER stress-induced cell death. In Aim 2, we will address if CMA plays a similar stress response role in vivo in a skeletal condition associated with ER stress, namely osteogenesis imperfecta (OI). The induction of macroautophagy has been shown to improve age- and aggregate-associated pathologies in other tissues. However, whether stimulation of autophagy can ameliorate skeletal pathologies is unknown. In OI, misfolded collagen forms aggregates and causes cellular stress. This is thought to decrease osteoblast function and contribute to the pathology of OI. In Aim3, we will increase macroautophagy capacity specifically in the osteoblast lineage cells and address if this clears collagen aggregates, relives ER stress, and improves OI skeletal pathology.

人们认为细胞应激源会引起成骨细胞谱系细胞（祖细胞，形成骨成骨细胞和重塑的编排骨细胞）的功能障碍或死亡，从而导致骨骼疾病的骨骼损失。自噬是一种细胞应激响应途径，可回收受细胞应激元素损坏的细胞成分。有三种类型的自噬：大自动噬菌，伴侣介导的自噬（CMA）和微自噬。这些不同类型的自噬在机制，目标和功能上不同。除应力反应外，自噬途径还具有细胞类型特异性功能，例如控制细胞分化。我们先前已经表明，大藻类和CMA有助于骨重塑，尽管在不同的水平上。在此，我们假设“自噬促进了成骨细胞细胞的分化，生存和功能”。在先前的研究中，我们已经表明缺乏大型噬菌会导致成骨细胞数量和骨形成减少。在AIM1中，我们将检查缺乏大型噬菌体减少成骨细胞数量和骨形成的可能机制。具体而言，我们将检查缺乏大噬菌学会改变成骨细胞细胞的增殖，凋亡或分化。我们的初步研究表明，成骨细胞使用CMA来防止ER应激诱导的细胞死亡。在AIM 2中，我们将在与ER应激相关的骨骼疾病（即成骨剂Imperfecta（OI））中扮演类似的应力反应作用。大量自噬的诱导已被证明可以改善其他组织中与年龄和骨料相关的病理。然而，自噬刺激是否可以改善骨骼病理是未知的。在OI中，错误折叠的胶原蛋白形成聚集体并引起细胞应激。人们认为这会降低成骨细胞功能，并有助于OI的病理。在AIM3中，我们将在成骨细胞谱系细胞中特别提高大噬菌能力，并解决这是否清除胶原蛋白聚集体，恢复ER应激并改善OI骨骼病理学。