Glucocorticoids, Bone Strength and Angiogenesis

糖皮质激素、骨强度和血管生成

• 批准号: 7785356
• 负责人: ROBERT Stewart WEINSTEIN
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7785356
• 关键词: Accounting; Acid Phosphatase; Address; Adherence; Adult; Affect; Agreement; Alendronate; Angiogenic Factor; Angiogenic Peptides; Animal Model; Animals; Apoptosis; Area; Attenuated; Biological Assay; Biopsy; Biopsy Specimen; Blood Vessels; Blood flow; Bone Density; Bone Diseases; Bone remodeling; Breathing; Calcium; Cell Culture Techniques; Cells; Cessation of life; Chest wall structure; Chronic; Collagen; Data; Deterioration; Dexamethasone; Disease; Dose; Endothelial Cells; Enzymes; Estrogens; Exhibits; Fracture; Funding; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Guidelines; HIF1A gene; Health; Healthcare; Hormones; Human; Hydroxysteroid Dehydrogenases; Hypoxia; Image; In Vitro; Intercellular Fluid; Investigation; Knowledge; Liquid substance; Lung diseases; Measurement; Messenger RNA; Metatarsal bone structure; Methodology; Minerals; Mission; Modeling; Molecular; Motivation; Mus; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Osteogenesis; Osteoid; Osteoporosis; Pain; Parathyroid gland; Pathogenesis; Patient Care; Patients; Perfusion; Pharmaceutical Preparations; Physical activity; Physicians; Plastics; Play; Postmenopausal Osteoporosis; Prevalence; Prevention; Process; Production; Proteins; Publishing; Raloxifene; Recruitment Activity; Research Design; Resistance; Respiratory physiology; Rib Fractures; Risk; Role; Site; Skeleton; Spinal Fractures; Splint Device; Staining method; Stains; Structure; Surface; System; Tartrates; Testing; Time; Tissues; Tracer; Transgenic Mice; Tube; Umbilical vein; Vascular Endothelial Growth Factors; Veterans; Vitamin D; Water; Weight; Woman; Work; abstracting; angiogenesis; base; bisphosphonate; bone; bone cell; bone loss; bone mass; bone strength; bone turnover; clinically significant; fetal; in vitro Assay; in vivo; innovation; insight; lead chromate; male; overexpression; prednisolone; prevent; promoter; public health relevance; research study; resilience; response; rib bone structure; skeletal; spine bone structure; tissue/cell culture; treatment strategy; vascular factor

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Glucocorticoid-induced osteoporosis is the most common drug-induced form of osteoporosis. Fractures may occur in 30 to 50% of patients receiving chronic glucocorticoid therapy but bone density measurements underestimate the risk of fracture in this disorder and account for, at least in part, the under- recognition and under-treatment of the disease. Vertebral and rib fractures are of particular importance to the VA patient care mission because in addition to causing pain and reducing physical activity, they can markedly decrease respiratory function in patients with pulmonary disease by causing splinting of the chest wall, thereby reducing the capacity to breathe. Glucocorticoid therapy causes a decline in bone strength that surpasses the decline in bone density, but little is known of the mechanism behind this phenomenon. Although it is widely appreciated that bone is composed of cells, mineral and collagen, it is seldom realized that water is another major component accounting for more than one fourth of the wet weight of bone. Fracture resistance of hard tissues is defective without water and water confers to bone much of its unique strength and resilience. The long-term objective of this proposal is to determine whether drug-induced deterioration of bone water and vascularity may account for the disproportionately greater decline in bone strength than in bone mass typical of glucocorticoid- induced osteoporosis and whether the bone strength and vascularity may be compromised through direct actions of glucocorticoids on bone cells. Studies aimed at the cellular and molecular mechanisms of the pathogenesis of the loss of bone strength in glucocorticoid-induced osteoporosis and investigation of the reasons for the limited response to current therapy would increase motivation to protect the skeleton as early as possible, before there are decreases in bone density. To achieve this goal, the direct effects of glucocorticoid excess on the expression of vascular proteins from bone cells will be investigated. Next, determination of the contribution of bone water and vascularity to the loss of bone strength in an animal model of glucocorticoid-induced osteoporosis and the additional impact of various treatment strategies to prevent glucocorticoid-induced osteoporosis will be examined. The clinical significance of these changes in bone vascular factors will be elucidated in humans using archival bone biopsy specimens obtained from patients with postmenopausal osteoporosis or glucocorticoid-induced osteoporosis. The studies proposed in this application are timely and by capitalizing on modern concepts and innovative methodology offer the opportunity for new insights that are sorely needed for the prevention and treatment of glucocorticoid-induced bone disease and are, therefore, immediately relevant and vital to the VA health care mission. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health: Fractures of the vertebrae or ribs are often the presenting manifestations of glucocorticoid-induced osteoporosis (GIO). Such fractures are of particular importance to the VA patient care mission because in addition to causing pain and reducing activity, they can markedly decrease respiratory function. In one center, adherence to published guidelines for the management of GIO was so low that only 8% of male veterans were given adequate calcium and vitamin D and less than 20% were given specific therapy. Reasons for this nonadherence include: 1) physicians underestimate the time glucocorticoids will be given and downplay the risk of GIO, 2) many physicians think osteoporosis is a disorder of women, and 3) bone density tests underestimate fracture risk in GIO. Thus, inadequate knowledge about GIO plays an important role in the mismanagement of the disease. The proposed studies aimed at the mechanisms of the loss of bone strength in GIO should provide new insights that are sorely needed and immediately vital to veterans health care.

描述（由申请人提供）： 项目摘要/摘要糖皮质激素诱导的骨质疏松症是最常见的药物诱导的骨质疏松症。 在接受慢性糖皮质激素治疗的患者中，可能发生骨折，但骨密度测量值低估了这种疾病中骨折的风险，并且至少部分地解释了这种疾病的不足和不足。 椎骨和肋骨骨折对于VA患者护理任务特别重要，因为除了引起疼痛和减轻体育活动外，它们还可以通过导致胸壁夹板来显着降低肺部疾病患者的呼吸功能，从而降低呼吸的能力。 糖皮质激素治疗会导致骨强度的下降，超过骨密度下降，但对这种现象背后的机制知之甚少。 尽管骨骼是由矿物和胶原蛋白组成的细胞组成的，但很少有人意识到水是另一个主要成分，占骨头湿重的四分之一以上。 硬组织的抗断裂性是有缺陷的，没有水和水赋予其独特的强度和弹性的大部分骨骼。 该提案的长期目标是确定药物诱导的骨水和血管恶化是否可能造成骨骼强度的不成比例下降，而不是典型的糖皮质激素诱导的骨质疏松症的骨骼质量和骨骼强度以及骨骼强度和血管性是否会因糖皮质激素对骨细胞的直接作用而损害。 针对糖皮质激素诱导的骨质疏松症中骨强度损失的细胞和分子机制的研究，以及对当前治疗反应有限的原因的研究将增加尽早保护骨骼的动机，然后骨密度降低。 为了实现这一目标，将研究糖皮质激素过量对骨细胞血管蛋白表达的直接影响。 接下来，将检查糖皮质激素诱导的骨质疏松症的动物模型中骨水和血管对骨强度损失的贡献，以及各种治疗策略的其他影响，以防止糖皮质激素诱导的骨质疏松症。 这些变化在骨血管因子中的临床意义将使用从绝经后骨质疏松症或糖皮质激素诱导的骨质疏松症的患者获得的档案骨活检标本中阐明人类。 本应用中提出的研究是及时的，并通过利用现代概念和创新方法为预防和治疗糖皮质激素引起的骨病所需的新见解提供了机会，因此与VA医疗保健任务有关。 公共卫生相关性： 与退伍军人健康的相关性：椎骨或肋骨的骨折通常是糖皮质激素诱导的骨质疏松症（GIO）的表现。这种断裂对于VA患者护理任务特别重要，因为除了引起疼痛和减轻活动外，它们还可以显着降低呼吸功能。在一个中心中，遵守已发表的GIO管理指南如此之低，以至于只有8％的男性退伍军人获得了足够的钙和维生素D，而少于20％的男性退伍军人得到了特定的治疗。 这种不遵守的原因包括：1）医生低估了将给出糖皮质激素的时间，并淡化了GIO的风险，2）许多医生认为骨质疏松症是女性的疾病，而3）骨密度测试低估了GIO的骨折风险。因此，对GIO的知识不足在疾病管理不善中起着重要作用。针对GIO骨骼强度丧失的机制的拟议研究应提供迫切需要的新见解，对退伍军人卫生保健至关重要。