Osteoclast-Osteocyte Interaction's in Paget's Disease

佩吉特病中破骨细胞与骨细胞的相互作用

基本信息

批准号：
10577740
负责人：
NORIYOSHI KURIHARA
金额：
$ 48.51万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-22 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577740
关键词：
Adult Affect Age Years Aging Animal Model Automobile Driving Bone Development Bone Diseases Bone Resorption Cells Characteristics Coupled Coupling DNA Sequence Alteration Data Dendrites Development Diagnosis Disputes Dose Ephrin-B2 Etiology Exposure to Home Homing IGF1 gene IL6 gene Innate Bone Remodeling Insulin-Like Growth Factor I Interleukin-6 Lesion Link Location Lytic Measles virus Measles virus nucleocapsid protein Modeling Molecular Morphology Mouse Protein Mus Nature Osteitis Deformans Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteolytic Paget&apos s Disease Paper Pathogenesis Patients Phase Population Process Proteins Publications Reporting Role Sampling Signal Transduction Site Skeleton TNFSF11 gene Tamoxifen Testing Transgenic Mice bone bone cell in vivo insight mouse model older patient osteoblast differentiation overexpression programs promoter protein expression senescence skeletal tartrate-resistant acid phosphatase

项目摘要

Project Summary/Abstract: Paget’s Disease (PD) is usually diagnosed in patients >50 years of age, and is characterized by focal bone lesions (PDLs) that progress from an initial lytic to a mixed osteolytic-osteoblastic phase, due to rapid new bone formation. PD patients rarely develop new PDLs beyond those present at diagnosis. The primary cellular abnormality in PD resides in the osteoclast (OCL). However, the mechanisms responsible for the highly focal nature of PDLs, why PD is diagnosed in elderly patients, especially in patients harboring genetic mutations linked to PD, and the mechanisms driving the exuberant resorption/formation in PD, are unclear. We showed that OCLs from 70% of PD patients express measles virus nucleocapsid protein (MVNP), and transgenic mice with MVNP targeted to OCLs (MVNP mice) develop PDLs and the abnormal OCLs characteristic of PD. MVNP- expressing OCLs and OCLs from PD patients are hyper-responsive to RANKL and express high IL-6 levels, which induce high levels of IGF1 in OCLs (OCL-IGF1) to promote osteoblast (OB) differentiation in MVNP mice. Importantly, OCLs from PD patients but not normal donors also express increased IL-6 and IGF1. We confirmed OCL-IGF1’s role in PD and normal bone remodeling in vivo by generating WT and MVNP mice with targeted deletion of Igf1 in OCLs. We found that MVNP mice but not MVNP mice lacking OCL-Igf1 developed PDLs. Thus, high OCL-IGF1 levels in PD may be required to induce PDLs. However, these results do not explain why PDLs occur in aging patients or animal models and persist locally for long periods. These observations are most readily explained by stochastic changes in a long-lived bone cell population, most likely osteocytes (OCys). In this proposal we will test the Hypothesis: that pagetic OCL precursors, which are hyper-responsive to RANKL, home to specific skeletal sites containing senescent, pre-lesional OCys that produce or induce locally increased RANKL. As PD-OCLs numbers increase, they hyper-secrete sufficient IL-6 and IGF-1 to decrease Sost/sclerostin, increase expression of Wnts, block OCy differentiation and act directly on OB to enhance new bone formation. In preliminary studies, we found that OCys in PD (PD-OCys) express lower levels of OCy maturation markers, and display markedly reduced dendritic processes. Further, the percentage of sclerostin+ OCys adjacent to PDLs in MVNP mice was significantly lower compared to MVNP mice without PDLs or WT mice, and that IGF1 suppressed sclerostin expression in OCys. Importantly, similar morphologic changes occurred in OCys in bone samples of a PD patient, but not a normal donor. These results suggest that OCys may be key contributors to the pathogenesis of PD. To further test this hypothesis, we will: Aim 1. Characterize OCL-IGF1’s effects in PD and PD-OCys, identify the molecular mechanisms involved, and test if increased OCL-IGF1 is sufficient to induce PDLs and PD-OCys. Aim 2. Determine the role of senescent OCys in the location, development, progression and persistence of PDLs and PD. We will assess if prolonged exposure of PD-OCLs to normal OCys, or shorter exposure to OCys in older mice suffices for PDLs to develop.

项目摘要/摘要：佩吉特病 (PD) 通常在年龄 >50 岁的患者中诊断出来，其特征是局灶性骨由于快速新生骨，病变（PDL）从最初的溶解阶段进展到溶骨-成骨混合阶段 PD 患者很少会出现超出诊断时存在的新 PDL。 PD 的异常存在于破骨细胞 (OCL) 中，然而，其机制是高度局灶性的。 PDL 的性质，为什么老年患者，尤其是携带基因突变的患者会诊断出 PD 我们还不清楚与 PD 相关的机制，以及驱动 PD 旺盛吸收/形成的机制。 70% PD 患者的 OCL 表达麻疹病毒核衣壳蛋白 (MVNP)，以及转基因小鼠 MVNP 靶向 OCL（MVNP 小鼠）会出现 PDL 和 PD 的异常 OCL 特征。表达 OCL 的 PD 患者的 OCL 对 RANKL 反应过度，并表达高水平的 IL-6，诱导 OCL 中高水平的 IGF1 (OCL-IGF1)，以促进 MVNP 小鼠的成骨细胞 (OB) 分化。重要的是，我们证实，来自 PD 患者而非正常供体的 OCL 也表达增加的 IL-6 和 IGF1。通过生成靶向的 WT 和 MVNP 小鼠，OCL-IGF1 在 PD 和体内正常骨重塑中的作用我们发现，缺乏 OCL-Igf1 的 MVNP 小鼠而非 MVNP 小鼠会出现 PDL。因此，PD 中的高 OCL-IGF1 水平可能需要诱导 PDL。但是，这些结果并不能解释原因。 PDL 发生在老年患者或动物模型中，并在局部持续很长时间。最容易解释为长寿骨细胞群（最有可能是骨细胞）的随机变化 (OCys) 在这个提案中，我们将测试假设：页面 OCL 前体，它们是高反应性的。 RANKL，是含有衰老、损伤前 OCys 的特定骨骼位点的所在地，这些 OCys 产生或诱导随着 PD-OCL 数量的增加，它们会过度分泌足够的 IL-6 和 IGF-1，以局部增加 RANKL。减少 Sost/sclerostin，增加 Wnts 表达，阻断 OCy 分化并直接作用于 OB 在初步研究中，我们发现PD中的OCys（PD-OCys）表达较低。 OCy 成熟标记物的水平，并显示出显着减少的树突过程。 MVNP 小鼠中与 PDL 相邻的硬化蛋白+ OCys 显着低于没有 PDLs 或 WT 小鼠，并且 IGF1 抑制 OCys 中的硬化蛋白表达，重要的是，相似的形态。 PD 患者的骨样本中 OCys 发生了变化，但正常供体的骨样本中并未发生这些变化。 OCys 可能是 PD 发病机制的关键因素为了进一步检验这一假设，我们将：目标 1。表征 OCL-IGF1 在 PD 和 PD-OCys 中的作用，确定所涉及的分子机制，并测试是否增加的 OCL-IGF1 足以诱导 PDL 和 PD-OCys 目标 2. 确定衰老 OCys 的作用。我们将评估 PDL 和 PD 的位置、发展、进展和持续性是否延长。 PD-OCL 暴露于正常 OCys，或年长小鼠较短时间暴露于 OCys 足以导致 PDL 的形成。