Glucocorticoid-induced osteonecrosis of the hip, osteocytes and canalicular fluid

糖皮质激素引起的髋部、骨细胞和小管液的骨坏死

• 批准号: 9339480
• 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: 2009-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339480
• 关键词: Accounting; Address; Adverse effects; Age-Years; Alendronate; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Asthma; Blood Vessels; Bone Density; Bone Diseases; Bone necrosis; Cells; Cessation of life; Characteristics; Clinical; Collagen; Consensus; Cortisone; Custom; Dentin; Deterioration; Development; Disease; Distal; Drug usage; Essential Drugs; Femur; Fracture; Funding; Glucocorticoid Receptor; Glucocorticoids; Goals; Head; Healthcare; Hip region structure; Human; Hypersensitivity; Image; Immunosuppressive Agents; In Situ; Individual; Inflammatory Bowel Diseases; Intervention; Investigation; Liquid substance; Longevity; Magnetic Resonance Imaging; Metatarsal bone structure; Methodology; Minerals; Mission; Modernization; Molecular; Motivation; Mus; Oral; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; PTH gene; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phosphoproteins; Physiologic pulse; Population; Porosity; Post-Traumatic Stress Disorders; Predisposition; Prednisone; Prevalence; Prevention; Preventive therapy; Resistance; Signal Transduction; Steroid therapy; Surface; System; TNFSF11 gene; Time; Tissues; Total Hip Replacement; Transgenes; Transgenic Mice; Veterans; Water; Weight; base; bone; bone mass; bone strength; bone turnover; density; end stage disease; experimental study; fetal; implantation; innovation; insight; mouse model; organ transplant rejection; prednisolone; prevent; public health relevance; resilience; skeletal; spine bone structure

DESCRIPTION (provided by applicant): Glucocorticoids are the most common cause of nontraumatic osteonecrosis of the hip, a crippling disorder that often leads to total hip replacement. Osteonecrosis, the in situ death of a segment of bone, develops in up to 40% of patients receiving systemic glucocorticoids, especially after the administration of intensive parenteral courses. Although the pathology of the end-stage disease has been partially described, the cellular and molecular mechanisms responsible for the development of glucocorticoid-induced osteonecrosis remain unidentified and there is little consensus on optimal intervention strategies. This is because the sequential pathological changes in clinically asymptomatic patients are unknown and an animal model that replicates the progression of the human disorder is absent. Glucocorticoid therapy causes a decline in bone strength that surpasses the decline in bone density, but the mechanism behind this phenomenon remains unknown. 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 objective of this proposal is to use a murine model of osteonecrosis of the femoral head to determine whether glucocorticoid- 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 osteonecrosis and whether the bone strength and vascularity may be compromised through the direct actions of glucocorticoids on osteocytes. Studies aimed at the cellular and molecular mechanisms of the pathogenesis of glucocorticoid-induced osteonecrosis and investigation of potential preventative therapy would increase motivation to protect the hip as early as possible. We hypothesize that glucocorticoid-induced osteonecrosis of the femoral head is primarily due to adverse effects on femoral head osteocytes because of reduced bone vascularity and canalicular fluid. To achieve this goal, osteocytes in transgenic mice will be shielded from administered glucocorticoids to determine if these animals are protected from osteonecrosis. In addition, mice expressing a hypersensitive glucocorticoid receptor in osteocytes will be examined to determine if osteonecrosis is exaggerated. Next, the impact of the administration of alendronate or intermittent PTH to prevent glucocorticoid-induced osteonecrosis will be examined. 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.

描述（由申请人提供）： 糖皮质激素是髋关节非创伤性肌肉症的最常见原因，这是一种残酷的疾病，通常会导致总髋关节置换。骨坏死，现场死亡 骨骼的一部分，多达40％接受全身糖皮质激素的患者，尤其是在接受强化肠胃外疗程之后。尽管部分描述了末期疾病的病理，但导致糖皮质激素诱导的骨坏死的细胞和分子机制仍然不明显，并且几乎没有达成最佳干预策略的共识。这是因为临床无症状患者的顺序病理变化是未知的，并且不存在重复人类疾病进展的动物模型。 糖皮质激素治疗会导致骨强度的下降，超过骨密度下降，但这种现象背后的机制仍然未知。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。该建议的目的是使用股骨头的染色染色模型来确定糖皮质激素诱导的骨水和血管的恶化是否可能导致骨强度的骨骼强度下降，而不是典型的骨骼质量下降的骨骼质量和糖皮质激素诱导的骨骼强度和血管均构成的骨骼强度是否可能造成骨骼强度和血管造成的行为。骨细胞。针对糖皮质激素诱导的截骨症发病机理的细胞和分子机制的研究和对潜在预防疗法的研究将增加动机以尽早保护髋关节。 我们假设糖皮质激素诱导的股骨头的截骨主要是由于骨血管性和口腔液的降低，主要是由于对股骨头骨细胞的不利影响。为了实现这一目标，转基因小鼠中的骨细胞将与施用的糖皮质激素相保护，以确定这些动物是否受到骨坏死的保护。此外，将检查表达骨细胞中超敏糖皮​​质激素受体的小鼠，以确定是否夸大了骨坏死。接下来，将检查丙膦酸盐或间歇性PTH对防止糖皮质激素诱导的骨坏死的影响。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。