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）：