Effects of aging on MIF-mediated migration of circulating osteoclast precursors to particle-induced osteolysis lesions

摘要 普遍认为，植入器械产生的植入物磨损颗粒会导致假体周围 骨质溶解，一种由破骨细胞介导的慢性炎症性骨吸收。越来越多的证据表明 老年人更容易发生骨质溶解迫切需要新的战略， 预防或治疗假体周围骨质溶解在美国的老龄化社会，然而， 对于与衰老相关的破骨细胞前体迁移，特别是向周围骨病变的迁移，仍然是难以捉摸的。 我们的前期研究表明巨噬细胞移动抑制因子（MIF）对血液具有趋化性 通过其同源受体CXCR 4在体外以及在体内的小鼠模型中循环破骨细胞前体， 颗粒诱导的颅盖骨溶解（Movila等，2016.此外，高迁移率族蛋白B1（HMGB 1）， 最近被鉴定为细胞衰老的中心介质，显著增强衰老引起的MIF分泌 而不是体外的年轻巨噬细胞。基于这些证据，我们假设HMGB 1/MIF 轴在循环CXCR 4 + OCP归巢到磨损颗粒诱导的溶骨性病变中起关键作用。 人口老龄化。在本申请中，特异性目的1被设计用于确定HMGB 1在增加的细胞凋亡中的作用。 颗粒诱导的老年小鼠颅骨骨质溶解假体周围巨噬细胞产生MIF。我们将 比较HMGB 1及其受体（TLR家族的先天免疫受体和晚期免疫受体）的作用， 糖基化终末产物[10]）相对于年轻人（两个 月龄）和老龄（24月龄）野生型动物，在体外和体内。在具体目标2中， 将阐明MIF促进循环OCP趋化性迁移的分子机制， 衰老动物中颗粒诱导的骨质溶解病变。我们将建立潜在的分子机制 MIF介导的OCP向年轻与老年小鼠骨质溶解病变的年龄依赖性募集（比较） 已知的MIF受体包括CD 74、CXCR 2和CXCR 4。为此目的，需要对物体的真实的时间运动进行研究。 将使用FDA批准的最新技术水平监测Csf 1 r-eGFP-敲入小鼠中的eGFP+ CD 11b + OCP Cellvizio（Mauna Kea Technologies）活体内窥镜成像技术。拟议的研究项目 代表了对循环OCP对颗粒诱导的骨溶解作用的首次研究之一 衰老生物体中的病变。此外，这项研究将提供一个范式转换框架， 针对老年人中磨损碎屑诱导的骨质溶解病变开发新疗法，靶向MIF 活动

ABSTRACT It is commonly accepted that implant wear particles, generated from the implant device, induce peri-prosthetic osteolysis, a form of chronic inflammatory bone resorption mediated by osteoclasts. Growing evidence suggests that older populations are more susceptible to bone osteolysis. There is a critical need for new strategies to prevent or treat peri-prosthetic osteolysis in the aging society of the U.S. However, the underlying mechanisms for aging-associated osteoclast precursor migration, especially to the peripheral bone lesions, remain elusive. Our earlier studies demonstrate that macrophage migration inhibitory factor (MIF) is chemotactic for blood circulating osteoclast precursors via its cognate receptor CXCR4 in vitro as well as in vivo in a mouse model of particle-induced calvaria osteolysis (Movila et al., 2016. JBMR).Also, the high mobility group protein B1 (HMGB1), recently identified as a central mediator of cellular senescence, significantly enhances MIF secretion from aging rather than young macrophages in vitro. Based on these lines of evidence, we hypothesize that the HMGB1/MIF axis plays a key role in the homing of circulating CXCR4+ OCPs to wear particle-induced osteolytic lesions in the aging population. In this application, Specific Aim 1 is designed to establish the role of HMGB1 in increased MIF production by peri-prosthetic macrophages of aging mice with particle-induced calvaria osteolysis. We will compare the role of HMGB1 and its receptors (TLR family of innate immune receptors and receptor for advanced glycation endproducts [RAGE]) relative to the release of MIF from peri-prosthetic macrophages of young (two month-old) and aged (twenty four month-old) wild type animals, both in vitro and in vivo. In Specific Aim 2, we will elucidate the molecular mechanisms by which MIF promotes chemotactic migration of circulating OCPs to particle-induced osteolysis lesions in senescent animals. We will establish the molecular mechanism underlying MIF-mediated age-dependent recruitment of OCPs to osteolysis lesions in young vs. aged mice by comparison of the known MIF receptors including, CD74, CXCR2 and CXCR4. For this purpose, real time locomotion of eGFP+CD11b+ OCPs in Csf1r-eGFP-knock-in mice will be monitored using FDA-approved state-of-the-art Cellvizio (Mauna Kea Technologies) intravital endoscopic imaging technology. The proposed research project represents one of the first investigations into the contribution of circulating OCPs to particle-induced bone lytic lesions in senescent organisms. Further, this study will provide a paradigm-shifting framework for the development of novel therapies against wear debris-induced osteolysis lesions in older people, targeting MIF activity.