Senescence of Pre-Osteoclasts in Non-Traumatic OA

非创伤性骨关节炎中前破骨细胞的衰老

基本信息

批准号：
10326804
负责人：
Mei Wan
金额：
$ 35.23万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326804
关键词：
Affect Age Aging Angiogenic Factor Ankle Apoptosis Attenuated Blood Vessels Bone Marrow Bone Marrow Cells Bone Tissue Cartilage Cell Aging Cell Cycle Arrest Cell Proliferation Cells Chronic Chronic Disease Clinical Research Degenerative polyarthritis Deterioration Development Diagnostic Disease Elderly Enrollment Frail Elderly Functional disorder Genes Genetic Goals Hand Osteoarthritis High Fat Diet Hip Osteoarthritis Human Joints Knee Osteoarthritis Knee joint Measures Mechanics Metabolic Metabolic syndrome Mononuclear Mus Musculoskeletal Diseases Obesity Osteoclasts Osteogenesis Pathogenesis Pathogenicity Patients Pharmacology Phenotype Physiologic Ossification Population Prevalence Reporter Risk Factors Role Skeleton Synovial Membrane Testing Tissues Transgenic Organisms Tube Vascular Endothelial Cell Work age related angiogenesis arthropathies articular cartilage bone bone cell cell type defined contribution driving force epidemiology study frailty functional loss genetic approach joint destruction joint injury metabolic phenotype mouse model novel osteoarthritis pain overexpression platelet-derived growth factor BB radiological imaging senescence subchondral bone treatment strategy

项目摘要

SUMMARY/ABSTRACT Osteoarthritis (OA) is the most prevalent age-associated chronic joint disease. Although direct joint injury and excessive mechanical overloading are considered as important contributors to the development of OA, only approximately 12% of the overall prevalence of symptomatic OA is attributable to posttraumatic OA of the hip, knee, or ankle. Aging is recognized as the most important risk factor for OA, and the metabolic phenotype becomes the second most frequent subtype of OA among patients enrolled in clinical studies. Recently, it has been recognized that cellular senescence is a key driver for the progression of post-traumatic OA. However, whether and how senescent cells (SnCs) are involved in the development of non-traumatic OA remain poorly understood. In our preliminary study, we found accumulated SnCs at the joint subchondral bone marrow of both spontaneous aging OA mice and STR/Ort mice, a spontaneous OA mice associated with metabolic dysregulation. Increased SnCs were not detected in subchondral bone marrow of a post-traumatic OA mice. Therefore, subchondral bone marrow cell senescence may represent a unique feature of non-traumatic subtype of OA distinguishable from post-traumatic OA. Moreover, we identified that close to 80% of the SnCs are bone marrow Pre-osteoclast (Pre-OC). Pre-OCs isolated from old mice, relative to young mice, had increased expression of common senescence-associated secretory phenotype (SASP) factors and much higher expression of angiogenesis factor PDGF-BB, a potent angiogenesis factor. It is known that increased subchondral bone angiogenesis is a major contributor to the development of OA. Therefore, the excessive PDGF-BB secreted by subchondral bone marrow SnCs may contribute to aberrant subchondral bone angiogenesis. Our central hypothesis is that senescent Pre-OCs induce aberrant subchondral bone angiogenesis by secreting excessive PDGF-BB, leading to OA-related joint structural damage. The hypothesis will be tested by the following Specific Aims. In Aim 1, we will trace the SnCs in synovial tissue, articular cartilage, and subchondral bone tissue of the joints by detecting the cellular senescence markers in spontaneous aging OA mice and STR/Ort mice. We will also trace the SnCs at different stages of OC lineage and verify the SASP phenotype of the cells in bone marrow of the mice. Aim 2 will examine the necessity and sufficiency of Pre-OCs-derived PDGF-BB in age-associated subchondral bone angiogenesis and OA development. In Aim 3, we will first define the contribution of cellular senescence to subchondral bone angiogenesis and osteogenesis by selectively eliminating the SnCs in OA mice. We will then test if blockage of Pre-OC senescence using both genetic and pharmacologic approaches attenuates OA progression.

摘要/摘要骨关节炎（OA）是最常见的与年龄相关的慢性关节疾病。虽然直接关节损伤和过度的机械超载被认为是 OA 发展的重要因素，只有大约 12% 的症状性 OA 总体患病率可归因于髋部创伤后 OA，膝盖或脚踝。衰老被认为是 OA 最重要的危险因素，代谢表型成为参加临床研究的患者中第二常见的 OA 亚型。近日，有人们认识到细胞衰老是创伤后骨关节炎进展的关键驱动因素。然而，衰老细胞 (SnC) 是否以及如何参与非创伤性 OA 的发展仍不清楚明白了。在我们的初步研究中，我们发现在两者的关节软骨下骨髓中积累了 SnC。自发性衰老 OA 小鼠和 STR/Ort 小鼠，自发性 OA 小鼠与代谢失调相关。在创伤后 OA 小鼠的软骨下骨髓中未检测到 SnC 增加。所以，软骨下骨髓细胞衰老可能代表非创伤性 OA 亚型的独特特征与创伤后 OA 不同。此外，我们发现接近 80% 的 SnC 是骨髓破骨细胞前体（Pre-OC）。与年轻小鼠相比，从老年小鼠中分离出的前 OCs 的表达增加常见的衰老相关分泌表型（SASP）因子和更高的表达血管生成因子PDGF-BB，一种有效的血管生成因子。众所周知，软骨下骨增加血管生成是 OA 发展的主要贡献者。因此，分泌过多的PDGF-BB 软骨下骨髓 SnCs 可能导致异常软骨下骨血管生成。我们的中央假设衰老的 Pre-OCs 通过分泌过多的脂质来诱导异常的软骨下骨血管生成 PDGF-BB，导致骨关节炎相关的关节结构损伤。该假设将通过以下具体内容进行检验目标。在目标 1 中，我们将追踪滑膜组织、关节软骨和软骨下骨组织中的 SnC。通过检测自发衰老 OA 小鼠和 STR/Ort 小鼠的细胞衰老标记物来研究关节。我们将还追踪 OC 谱系不同阶段的 SnC，并验证骨髓中细胞的 SASP 表型老鼠的。目标 2 将检验 Pre-OCs 衍生的 PDGF-BB 在与年龄相关的疾病中的必要性和充分性软骨下骨血管生成和 OA 发展。在目标 3 中，我们将首先定义细胞的贡献通过选择性消除 OA 小鼠中的 SnCs 来影响软骨下骨血管生成和骨生成的衰老。然后，我们将测试是否使用遗传和药理学方法来阻断 Pre-OC 衰老减缓 OA 的进展。