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: 8912853
• 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/8912853
• 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; Health; Healthcare; Hip region structure; Hormones; Human; Image; Immunosuppressive Agents; In Situ; Individual; Inflammatory Bowel Diseases; Intervention; Investigation; Liquid substance; Longevity; Magnetic Resonance Imaging; Metatarsal bone structure; Methodology; Minerals; Mission; Modeling; Molecular; Motivation; Mus; Oral; Organ Transplantation; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Parathyroid gland; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phosphoproteins; Physiologic pulse; Population; Porosity; Post-Traumatic Stress Disorders; Predisposition; Prednisone; Prevalence; Prevention; Resistance; Signal Transduction; Steroid therapy; Surface; System; TNFSF11 gene; Tissues; Total Hip Replacement; Transgenes; Transgenic Mice; Vascular Endothelial Growth Factors; Veterans; Water; Weight; base; bone; bone mass; bone strength; bone turnover; density; end stage disease; fetal; implantation; innovation; insight; mouse model; prednisolone; prevent; research study; 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）： 糖皮质激素是非创伤性髋部骨坏死的最常见原因，这是一种严重的疾病，通常会导致全髋关节置换术。骨坏死，即原位死亡 在接受全身性糖皮质激素治疗的患者中，高达 40% 的患者会出现骨段，尤其是在强化肠外疗程后。尽管终末期疾病的病理学已得到部分描述，但导致糖皮质激素诱导的骨坏死发生的细胞和分子机制仍不清楚，并且对于最佳干预策略几乎没有达成共识。这是因为临床无症状患者的连续病理变化是未知的，并且缺乏复制人类疾病进展的动物模型。 糖皮质激素治疗导致骨强度下降超过骨密度下降，但这种现象背后的机制仍不清楚。尽管人们普遍认为骨骼是由细胞、矿物质和胶原蛋白组成，但很少意识到水是另一种主要成分，占骨骼湿重的四分之一以上。如果没有水，硬组织的抗断裂能力就会出现缺陷，而水赋予骨骼许多独特的强度和弹性。本提案的目的是使用股骨头坏死的小鼠模型来确定糖皮质激素诱导的骨水和血管供应的恶化是否可以解释骨强度的下降比糖皮质激素诱导的骨坏死典型的骨量的下降更大，以及骨强度和血管供应是否可能通过糖皮质激素对股骨头的直接作用而受到损害。 骨细胞。针对糖皮质激素引起的骨坏死发病机制的细胞和分子机制的研究以及潜在预防治疗的研究将增加尽早保护髋关节的动力。 我们假设糖皮质激素引起的股骨头坏死主要是由于骨血管供应和骨小管液减少而对股骨头骨细胞产生不利影响。为了实现这一目标，转基因小鼠的骨细胞将免受糖皮质激素的影响，以确定这些动物是否免受骨坏死的影响。此外，还将检查骨细胞中表达超敏糖皮质激素受体的小鼠，以确定骨坏死是否被夸大。接下来，将检查阿仑膦酸钠或间歇性 PTH 给药对预防糖皮质激素引起的骨坏死的影响。本申请中提出的研究是及时的，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急需的新见解提供了机会，因此与退伍军人管理局的医疗保健使命直接相关且至关重要。