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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：
10556420
负责人：
Mei Wan
金额：
$ 34.97万
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/10556420
关键词：
Acceleration Affect Age Aging Angiogenic Factor Ankle Apoptosis Attenuated Blood Vessels Bone Marrow Bone Marrow Cells Bone Resorption Bone Tissue Cartilage Cell Aging Cell Cycle Arrest Cell Proliferation Cells Chronic Chronic Disease Clinical Research Deceleration Degenerative polyarthritis Deterioration Development Diagnostic Disease Elderly Frail Elderly Functional disorder Genes Genetic Goals Hand Osteoarthritis High Fat Diet Hip Osteoarthritis Human Invaded Joints Knee Osteoarthritis Knee joint Measures Mechanics Metabolic Metabolic syndrome Mononuclear Mus Musculoskeletal Diseases Nuclear Obesity Osteoclasts Osteogenesis Pathogenesis Pathogenicity Phenotype Physiologic Ossification Population Prevalence Reporter Risk Factors Role Skeleton Synovial Membrane Testing Tissues Transgenic Organisms Traumatic Arthropathy Tube Vascular Endothelial Cell Work age related angiogenesis arthropathies articular cartilage 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 participant enrollment pharmacologic 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/文摘