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.

项目摘要/摘要 流动性降低显着增加了许多慢性疾病的风险，导致加速 正常老化过程。骨骼变性，特别是脊柱和关节的变性，是最普遍的 疾病导致流动性下降和脆弱。脆弱，定义为生理储备降低的状态， 通常会随着衰老而发展，并影响一个人弥补疾病额外燃烧的能力。 随着脆弱的发展，自然的体内稳态储备降低了，身体有能力补偿 为了减少扰动。脊柱和关节的变性可以显着加速 脆弱；但是，这种衰老和发展中这种退化的基本病理生理学以及 尚不清楚产生的腰痛（LBP）和骨关节炎（OA）的进展。没有疾病 - 修改两者的治疗，主要是由于对疼痛病理生理学的理解缺乏 OA亚型之间的独特细胞信号传导变化。 LBP通常是由于两性脊柱关节的变性而导致的，疼痛与疼痛最相关 随着椎骨终板形态的变化。腹膜关节的变性是一组多种过程 在伞术语“骨关节炎”下经常混合在一起，但代表异质 疾病过程。两种椎骨终结物和软骨下骨的破骨细胞（OC）均经历衰老 在衰老期间产生多孔硬化终结物，在软骨下骨中未偶联，感觉 OC秘密Netrin-1诱导可能导致疼痛的轴突延伸和神经。因此，我们 假设通过 感觉oC导致骨骼关节变性和疼痛，严重限制活动能力并增加 脆弱地加速衰老。在项目1中，我们将研究末端孔隙率如何诱导脊柱 变性和感觉神经导致LBP。在项目2中，我们将研究 间歇性甲状旁腺激素注射（IPTH）的翻译应用 - 椎间盘增加（IVD） 通过重塑多孔硬化，脊柱变性并减少终板神经支配和LBP 终结。在项目3中，我们将表征两个不同亚型的细胞感应机理 OA：通过oc前感应的非创伤性OA。一起，这三个项目，由 常见的行政和生物统计学（核心A）以及体内模型和组织学（核心B）核心将导致 在细微的理解与衰老相关的关节和脊柱变性的病理生理学中 为潜在的治疗靶标提供基本的机械见解。