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

描述（由申请人提供）： 糖皮质激素是非创伤性髋关节骨坏死的最常见原因，这是一种致残性疾病，通常导致全髋关节置换术。骨坏死，即一种 在接受全身性糖皮质激素治疗的患者中，高达40%的患者会出现骨节段，尤其是在强化胃肠外疗程后。虽然终末期疾病的病理学已部分描述，糖皮质激素诱导的骨坏死的发展负责的细胞和分子机制仍然不明，有最佳的干预策略很少达成共识。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，但这一现象背后的机制仍不清楚。虽然人们普遍认为骨是由细胞、矿物质和胶原蛋白组成的，但很少意识到水是另一种主要成分，占骨湿重的四分之一以上。硬组织的抗断裂性在没有水的情况下是有缺陷的，并且水赋予骨许多其独特的强度和弹性。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的恶化是否可以解释骨强度比糖皮质激素诱导的骨坏死典型的骨量不成比例地更大的下降，以及骨强度和血管是否可以通过糖皮质激素对骨细胞的直接作用而受到损害。针对糖皮质激素诱导的骨坏死发病机制的细胞和分子机制的研究以及潜在的预防性治疗的调查将增加尽早保护髋关节的动机。 我们假设糖皮质激素诱导的股骨头坏死主要是由于骨血管和小管液减少对股骨头骨细胞的不良影响。为了实现这一目标，转基因小鼠中的骨细胞将被屏蔽而不受糖皮质激素的施用，以确定这些动物是否被保护免于骨坏死。此外，将检查在骨细胞中表达超敏糖皮质激素受体的小鼠，以确定骨坏死是否加重。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诱导的骨坏死的影响。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，为糖皮质激素诱导的骨病的预防和治疗迫切需要的新见解提供了机会，因此，与VA医疗保健使命直接相关且至关重要。

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.