Skeleton and Joint Degeneration with Aging

项目摘要/摘要 行动不便会显著增加罹患多种慢性病的风险，从而加速 正常的老化过程。骨骼退行性变，特别是脊柱和关节退行性变是最常见的 导致行动能力下降和虚弱的疾病。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，并影响一个人补偿额外疾病负担的能力。 随着虚弱的发展，自然的动态平衡储备减少，身体的补偿能力 对于微扰的影响是减少的。脊椎和关节的退化可以大大加速 然而，这种衰老和发育退化的潜在病理生理学 由此导致的腰痛(LBP)和骨关节炎(OA)的进展情况尚不清楚。没有疾病- 修改治疗方法，很大程度上是由于对疼痛的病理生理学和 独特的细胞信号在不同的OA亚型之间变化。 腰痛通常是由双关节脊柱关节退变引起的，其中疼痛的相关性最强。 并伴有椎体终板形态的改变。腹泻性关节退变是一系列不同的过程。 这些疾病通常被归类为“骨关节炎”，但它们代表着一种异质性 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硬化性终板，软骨下骨的解偶联重塑，以及衰老 OC分泌Netrin-1以诱导轴突挤压和神经支配，从而可能导致疼痛。因此，我们 多孔硬化性终板与软骨下骨解偶联改建的假说 衰老的OC会导致骨骼关节退变和疼痛，严重限制活动和增加 虚弱加速衰老。在项目1中，我们将研究终板孔洞如何随着年龄的增长而导致脊柱 退化和感觉神经支配导致腰痛。在项目2中，我们将研究 间歇注射甲状旁腺激素(IPTH)增高型间盘(IVD)的翻译性应用 多孔性硬化重建对脊髓体积和终板神经支配及LBP的影响 端板。在项目3中，我们将描述两种不同亚型的细胞衰老的机制。 骨性关节炎：非创伤性骨质疏松症，是由骨质疏松症前期的衰老引起的。这3个项目加起来，由 将产生共同行政和生物统计学(核心A)和活体模型和组织学(核心B)核心 对与衰老和意志相关的关节和脊柱退变的病理生理学有细微的理解 为潜在的治疗靶点提供基础性的机制洞察。

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.