Skeleton and Joint Degeneration with Aging

骨骼和关节随衰老而退化

• 批准号: 10326799
• 负责人: Xu Cao
• 金额: $ 187.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10326799
• 关键词: Acceleration; Address; Age; Aging; Arthralgia; Arthritis; Axon; Basic Science; Biometry; Biostatistics Core; Bone Marrow; Cause of Death; Cell Aging; Cells; Chronic Disease; Consensus; Degenerative polyarthritis; Development; Discipline; Disease; Experimental Models; Foundations; Functional disorder; Future; Histology; Human; Individual; Injections; Intervertebral disc structure; Joints; Lead; Life Expectancy; Longevity; Low Back Pain; Mechanics; Medical; Morphology; Mus; NTN1 gene; Nerve; Osteoclasts; PTH gene; Pain; Pathogenesis; Patients; Persons; Physicians; Physiologic Ossification; Physiological; Play; Population; Porosity; Positioning Attribute; Process; Program Research Project Grants; Quality of life; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Scientist; Sclerosis; Secretory Cell; Sensory; Signal Transduction; Skeleton; Spinal; Spine pain; Therapeutic; Training; Transforming Growth Factors; Universities; Vertebral column; Work; aged; angiogenesis; articular cartilage; burden of illness; calcification; cost; frailty; functional decline; in vivo; in vivo Model; insight; joint destruction; macrophage; medical schools; mouse model; nerve supply; normal aging; pain behavior; pain reduction; platelet-derived growth factor BB; senescence; skeletal; spine bone structure; subchondral bone; therapeutic target; translational applications

PROJECT SUMMARY/ABSTRACT Decreased mobility significantly increases the risk of many chronic diseases leading to an acceleration of the normal aging process. Skeletal degeneration, particularly of the spine and joints, are among the most prevalent diseases leading to a decline in mobility and to frailty. Frailty, defined as a state of decreased physiologic reserve, often develops with aging and influences a person’s ability to compensate for the additional burden of disease. With development of frailty, the natural homeostatic reserve is reduced and the ability of the body to compensate for perturbations is reduced. Degeneration of the spine and joints can substantially accelerate development of frailty; however, the underlying pathophysiology of this degeneration in aging and the development and progression of resulting low back pain (LBP) and osteoarthritis (OA) is not well understood. There is no disease- modifying treatment for either, largely due to the lack in the understanding of pathophysiology of pain and the unique cellular signaling changes among OA subtypes. LBP commonly results from degeneration of the amphiarthrodial spinal joints, with pain correlating most strongly with changes in vertebral endplate morphology. Degeneration of diarthrodial joints is a set of diverse processes that are frequently lumped together under the umbrella term “osteoarthritis” but represent a heterogeneous disease process. Osteoclasts (OC) in both vertebral endplates and subchondral bone undergo senescence during aging to generate porous sclerotic endplates, uncoupled remodeling in subchondral bone, and senescent OC secrete Netrin-1 to induce axonal extrusion and innervation that potentially lead to pain. Therefore, we hypothesize that porous sclerotic endplates and uncoupled remodeling of subchondral bone by senescent OC lead to skeletal joint degeneration and pain, severely limiting mobility and increasing frailty to accelerate aging. In Project 1, we will investigate how endplate porosity with aging induces spinal degeneration and sensory innervation to result in LBP. In Project 2, we will investigate the mechanism of the translational application of intermittent parathyroid hormone injection (iPTH) – increased intervertebral disc (IVD) volume to spinal degeneration and reduce endplate nerve innervation and LBP by remodeling of porous sclerotic endplates. In Projects 3, we will characterize the mechanism of cellular senescence in two different subtypes of OA: non-traumatic OA that is orchestrated by senescence of pre-OC. Together, these 3 projects, supported by common Administrative and Biostatistics (Core A) and In Vivo Model and Histology (Core B) Cores, will result in nuanced understanding of the pathophysiology of joint and spinal degeneration associated with aging and will provide foundational mechanistic insights for potential therapeutic targets.

项目总结/摘要 活动能力的下降大大增加了许多慢性疾病的风险，导致疾病的加速。 正常的衰老过程。骨骼退化，特别是脊柱和关节的退化，是最普遍的 导致活动能力下降和身体虚弱的疾病。虚弱，定义为生理储备减少的状态， 通常随着年龄的增长而发展，并影响一个人补偿疾病额外负担的能力。 随着虚弱的发展，自然的自我平衡储备减少，身体的补偿能力下降， 因为扰动减少了。脊柱和关节的退化可以大大加速 然而，这种退化在衰老和发育中的潜在病理生理学， 引起的下背痛（LBP）和骨关节炎（OA）的进展尚不清楚。没有疾病- 修改治疗，主要是由于缺乏对疼痛的病理生理学的理解， OA亚型之间独特的细胞信号传导变化。 腰椎间盘突出症通常是由椎关节退变引起的，与疼痛密切相关 椎体终板形态改变。关节退行性变是一系列不同的过程 这些疾病经常被统称为"骨关节炎"，但代表了一种异质性的骨关节炎。 疾病过程。椎体终板和软骨下骨中的破骨细胞（OC）经历衰老 在老化过程中产生多孔软骨终板，在软骨下骨中进行非偶联重塑， OC分泌Netrin-1诱导轴突挤出和神经支配，可能导致疼痛。所以我们 假设多孔软骨终板和软骨下骨非偶联重建 衰老的OC导致骨骼关节退化和疼痛，严重限制了活动性， 加速衰老的弱点在项目1中，我们将研究终板多孔性如何随着年龄的增长而诱导脊柱 变性和感觉神经支配导致LBP。在项目2中，我们将研究 间歇性甲状旁腺激素注射（iPTH）的转化应用-椎间盘（IVD）增加 通过重建多孔性骨质减少终板神经支配和LBP 终板在项目3中，我们将描述两种不同亚型的细胞衰老机制， OA：由前OC衰老引起的非创伤性OA。这三个项目由 将产生通用管理和生物统计学（核心A）和体内模型和组织学（核心B）核心 在微妙的理解与衰老和意志有关的关节和脊柱退化的病理生理学 为潜在的治疗靶点提供基础机制见解。