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.

项目概要/摘要 活动能力下降会显着增加许多慢性疾病的风险，从而导致加速 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虚弱的疾病，被定义为生理储备下降的状态， 通常随着年龄的增长而发展，并影响一个人补偿额外疾病负担的能力。 随着身体虚弱的发展，自然稳态储备降低，身体补偿能力下降 脊柱和关节的退化可以大大加速发育。 虚弱；然而，这种衰老和发育退化的潜在病理生理学 由此产生的腰痛 (LBP) 和骨关节炎 (OA) 的进展尚不清楚。 修改治疗方法，很大程度上是由于缺乏对疼痛的病理生理学和疼痛的理解 OA 亚型之间独特的细胞信号传导变化。 LBP 通常是由双关节脊柱关节退化引起的，与疼痛相关性最强 随着椎体终板形态的变化，关节退变是一系列不同的过程。 这些疾病经常被归为“骨关节炎”这一总称，但代表了一种异质性的疾病 椎体终板和软骨下骨中的破骨细胞（OC）经历衰老。 衰老过程中产生多孔硬化终板、软骨下骨的非耦合重塑和衰老 OC 分泌 Netrin-1 来诱导轴突挤压和神经支配，从而可能导致疼痛。 培养了多孔硬化终板和软骨下骨的非耦合重塑 衰老的 OC 会导致骨骼关节退化和疼痛，严重限制活动能力并增加 在项目 1 中，我们将研究终板孔隙随衰老如何诱发脊柱。 退化和感觉神经支配导致 LBP 在项目 2 中，我们将研究其机制。 间歇性甲状旁腺激素注射（iPTH）的转化应用——增加椎间盘（IVD） 通过重塑多孔硬化来减少脊柱退变的体积并减少终板神经支配和腰痛 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 的衰老精心策划的非创伤性 OA，这 3 个项目共同得到支持。 共同的管理和生物统计学（核心 A）以及体内模型和组织学（核心 B）核心，将产生 细致入微地了解与衰老和意志相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的见解。