Skeleton and Joint Degeneration with Aging

骨骼和关节随衰老而退化

• 批准号: 10556410
• 负责人: Xu Cao
• 金额: $ 184.37万
• 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/10556410
• 关键词: Acceleration; Address; Age; Aging; Arthralgia; Arthritis; Axon; Basic Science; Biometry; Bone Marrow; Cause of Death; Cell Aging; Cells; Chronic Disease; Compensation; Consensus; Degenerative polyarthritis; Development; Discipline; Disease; Experimental Models; Functional disorder; Future; Histology; Human; Individual; Injections; Intervertebral disc structure; Joints; Lead; Life Expectancy; Longevity; Low Back Pain; Macrophage; Modeling; 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; Therapeutic; Training; Transforming Growth Factors; Traumatic Arthropathy; United States; Universities; Vertebral column; Work; aged; angiogenesis; articular cartilage; burden of illness; calcification; cost; disability; frailty; functional decline; improved; in vivo; in vivo Model; insight; joint destruction; mechanical load; medical attention; 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/文摘