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

• 批准号: 10179554
• 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
• 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/10179554
• 关键词: Acute Pain; Adult; Affect; Animal Model; Arthritis; Asthma; Basic Science; Binding; Blood; Blood Vessels; Blood capillaries; Blood flow; Bone necrosis; Cell Line; Cell Lineage; Cells; Child; Chronic; Chronic Obstructive Airway 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; Joints; Knock-out; Knowledge; Longevity; Maintenance; Malignant Neoplasms; Mediating; Medical; Metabolic; Metaphysis; Mus; NF-kappa B; Neck; Nutrient; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Platelet-Derived Growth Factor; Prevalence; Reporting; Role; Shunt Device; Signal Pathway; Signal Transduction; Site; Skeleton; Speed; Steroids; Therapeutic Intervention; Tissues; Transgenic Mice; Translational Research; Tube; Up-Regulation; Vulnerable Populations; Wild Type Mouse; Work; angiogenesis; base; bone; cell type; chronic pain; efficacy evaluation; in vivo; insight; long bone; mouse model; overexpression; platelet-derived growth factor BB; potential biomarker; precursor cell; prednisolone; prevent; promoter; recruit; side effect; skeletal; targeted treatment; therapeutic development; tibia; wasting

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 糖皮质激素的骨毒性副作用，如骨质疏松症和骨坏死，限制了临床使用。儿童 是一个特别脆弱的人群，因为30-50%的儿童长期糖皮质激素发展成骨毒性， 没有FDA批准的儿童治疗方法。尽管有大量的研究 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，在不断增长的骨架。骨，特别是生长中的骨，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组织学特征是骨减少 脉管系统糖皮质激素抑制骨骼血管生成与骨骼脆性的关系 模型本研究的目的是阐明关键受影响的细胞和细胞内信号机制 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 建立幼龄糖皮质激素骨毒性小鼠模型。我们发现糖皮质激素 减少H型血管，一种与骨生成相关的特殊血管亚型。根据我们之前 研究表明，Trap+破骨细胞前体分泌血小板衍生生长因子BB型（PDGF-BB）， 招募内皮前体细胞（EPCs）形成H型血管，我们发现糖皮质激素抑制 通过干扰核因子κ β（NF-κB）与Pdgfb启动子的结合来抑制Pdgfb转录。 PDGF-BB的减少与H型血管数量的减少、成熟血管数量的减少有关。 成骨细胞和骨量减少。我们假设糖皮质激素抑制破骨细胞前体 PDGF-BB通过NF-κB的失活是糖皮质激素损害骨骼血管生成的原因。在这 建议，我们将剖析糖皮质激素抑制血管生成的关键细胞机制。 具体来说，我们将1）证明破骨细胞是糖皮质激素抑制的主要细胞类型， 骨骼血管生成2)探讨糖皮质激素抑制NF-κ B介导的细胞凋亡的机制 前破骨细胞Pdgfb转录。3)检查增加破骨细胞前体PDGF-BB预防 糖皮质激素抑制骨骼血管生成。骨特异性调节因子的测定 血管生成，这是至关重要的生长骨骼，将允许有针对性的药物治疗，以治疗和/或预防 儿童糖皮质激素的骨毒性副作用。此外，确定的机制， 糖皮质激素对血管生成的抑制将推进我们的基础知识，并扩大未来的研究 特别是骨坏死，帮助药物开发治疗干预，并提供深入了解 长期使用糖皮质激素观察到的其他脱靶组织副作用的机制。