Role of glucocorticoid-suppression of preosteoclast PDGF-BB in skeletal angiogenesis

糖皮质激素抑制前破骨细胞 PDGF-BB 在骨骼血管生成中的作用

基本信息

批准号：
10594402
负责人：
Janet Crane
金额：
$ 36.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594402
关键词：
Acute Pain Adult Affect Animal Model Arthritis Asthma Basic Science Binding Blood Blood Vessels Blood capillaries Blood flow Bone Growth Bone necrosis Cell Line Cell Lineage Cells Child Chronic Chronic Obstructive Pulmonary Disease Clinical Deformity Diagnosis Distal Dose Drug Targeting Endothelium Epiphysial cartilage Exceptional Child FDA approved Femur Functional disorder Future Genetic Genetic Transcription Glucocorticoid Receptor Glucocorticoids Graft Rejection Growth Health Histologic Hypersensitivity Impairment Incidence Inflammatory Bowel Diseases Knock-out Knowledge Longevity Lung Transplantation Maintenance Malignant Neoplasms Mediating Medical Metabolic Metaphysis Mus NF-kappa B Neck Nutrient Osteoblasts Osteoclasts Osteogenesis Osteoporosis Patients Persons Pharmaceutical Preparations Pharmacotherapy Phenotype Platelet-Derived Growth Factor Prevalence Replacement Arthroplasty Reporting Role Shunt Device Signal Pathway Signal Transduction Site Skeleton Speed Steroids Therapeutic Intervention Tissues Transgenic Mice Translational Research Tube Up-Regulation Vascularization Vulnerable Populations Wild Type Mouse Work angiogenesis bone cell type chronic pain efficacy evaluation in vivo insight long bone mouse model overexpression potential biomarker precursor cell prednisolone prevent promoter recruit side effect skeletal targeted treatment therapeutic development tibia wasting

项目摘要

Project Summary Osteotoxic side effects of glucocorticoids, such as osteoporosis and osteonecrosis, limit clinical use. Children are a particularly vulnerable population as 30-50% of children on chronic glucocorticoids develop an osteotoxic side effect and there are no-FDA approved treatments for children. Although there have been extensive studies about glucocorticoid effects on the bone in the mature skeleton focusing largely on osteoclasts and osteoblasts, knowledge gaps still exist which in the growing skeleton. Bone, particularly growing bone, is highly vascularized. A unifying histological feature of osteoporosis, osteonecrosis, and impaired skeletal growth, is reduced bone vasculature. Glucocorticoids impair skeletal angiogenesis, which correlates with skeletal fragility in animal models. The purpose of this study is to elucidate the key affected cell and intracellular signaling mechanism involved in glucocorticoid suppression of angiogenesis and its relation to osteotoxic side effects. We have established a young glucocorticoid-osteotoxic mouse model. We have found that glucocorticoids drastically reduce type H vessels, a specific subtype of blood vessels associated with osteogenesis. Building on our prior work demonstrating that Trap+ preosteoclasts secrete platelet-derived growth factor type BB (PDGF-BB), which recruits endothelial precursor cells (EPCs) to form type H blood vessels, we found that glucocorticoids suppress Pdgfb transcription by interfering with binding of nuclear factor kappa beta (NF-κB) to the Pdgfb promoter. Decreased PDGF-BB was associated with a decreased number of type H vessels, number of mature osteoblasts, and decreased bone volume. We hypothesize that glucocorticoid suppression of preosteoclast PDGF-BB via inactivation of NF-κB is the cause of glucocorticoid impairment of skeletal angiogenesis. In this proposal, we will dissect the key cellular mechanism involved in glucocorticoid suppression of angiogenesis. Specifically, we will 1) Demonstrate preosteoclasts are the major cell type in glucocorticoid-suppression of skeletal angiogenesis. 2) Determine the mechanism of glucocorticoid-suppression of NF-κB-mediated preosteoclast Pdgfb transcription. 3) Examine efficacy of increasing preosteoclast PDGF-BB for preventing glucocorticoid-suppression of skeletal angiogenesis. Determination of bone-specific factors that regulate angiogenesis, which is critical to the growing skeleton, will allow targeted drug therapy to treat and/or prevent osteotoxic side effects of glucocorticoids in children. Furthermore, identification of the mechanism of glucocorticoid-suppression of angiogenesis will advance our fundamental knowledge and expand future studies specifically on osteonecrosis, aid in drug-development for therapeutic interventions, and provide insight into mechanisms of other off-target tissue side effects observed with chronic glucocorticoid usage.

项目摘要糖皮质激素（例如骨质疏松症和骨坏死）的骨毒性副作用限制了临床使用。孩子们是一个特别脆弱的人群，因为慢性糖皮质激素的儿童中有30-50％发生骨毒素副作用和未经FDA的儿童批准治疗。尽管有广泛的研究关于糖皮质激素对成熟骨骼中骨骼的影响，主要集中在破骨细胞和成骨细胞上，知识差距仍然存在于成长中的骨骼中。骨骼，尤其是生长的骨骼，是高度血管化的。骨质疏松症，骨坏死和骨骼生长受损的统一的组织学特征是骨脉管系统。糖皮质激素会损害骨骼血管生成，该骨骼血管生成与动物的骨骼脆弱性相关型号。这项研究的目的是阐明受影响的细胞和细胞内信号传导机制参与糖皮质激素抑制血管生成及其与骨毒性副作用的关系。我们有建立了一个年轻的糖皮质激素蛋白毒性小鼠模型。我们发现糖皮质激素急剧减少H型血管，这是与成骨相关的血管的特定亚型。建立在我们先前的表明陷阱+前骨前血小板衍生的生长因子型BB（PDGF-BB）的工作，招募内皮前体细胞（EPC）形成H型血管，我们发现糖皮质激素抑制 PDGFB转录通过干扰核因子Kappaβ（NF-κB）与PDGFB启动子的结合。 PDGF-BB降低与H型血管数量减少有关，成熟数量成骨细胞和改善的骨体积。我们假设糖皮质激素抑制前骨前球体通过NF-κB灭活PDGF-BB是骨骼血管生成的糖皮质激素损害的原因。在这个提案，我们将剖析与糖皮质激素抑制血管生成有关的关键细胞机制。具体而言，我们将1）证明前细胞是糖皮质激素抑制的主要细胞类型骨骼血管生成。 2）确定NF-κB介导的糖皮质激素抑制的机制 pDGFB前pDGFB转录。 3）检查提高前pdgf-bb的效率以防止骨骼血管生成的糖皮质激素抑制。确定调节骨特异性因素血管生成对于不断增长的骨骼至关重要，将允许有针对性的药物治疗和/或预防糖皮质激素对儿童的骨毒性副作用。此外，识别机制血管生成的糖皮质激素抑制将促进我们的基本知识并扩大未来的研究特别了解骨坏死，有助于药物开发治疗干预措施，并洞悉慢性糖皮质激素使用观察到的其他脱靶组织副作用的机制。