GLUCOCORTICOIDS ALTER THE BIRTH & DEATH OF OSTEOBLASTS

高皮质醇血症对骨骼的不良影响已经被认识了60多年，但这些变化的确切细胞和分子基础仍然不清楚，有效的治疗方法仍然难以捉摸。糖皮质激素诱导的骨质疏松症的一个主要特征是骨形成减少。此外，接受长期糖皮质激素治疗的患者有时会出现股骨头塌陷（骨坏死）。股骨近端分离节段骨形成减少和原位死亡提示糖皮质激素过量可能改变骨细胞的出生和死亡。在导致这一应用的初步研究中，已经确定：(1)雄性瑞士韦伯斯特小鼠是糖皮质激素诱导的骨病的有效和信息模型，不会与体重减轻或性类固醇缺乏相混淆；(2)在小鼠和人类中，慢性糖皮质激素给药对骨骼的许多影响可以通过成骨细胞前体出生减少和成熟成骨细胞和骨细胞凋亡增加来解释。(3)减少成骨细胞凋亡，而不是增加成骨细胞生成，是间歇性给予甲状旁腺激素（PTH）刺激骨形成的机制，这一效应可用于研究糖皮质激素诱导的细胞凋亡的影响。为了验证糖皮质激素过量对骨骼的不利影响是由于骨髓中新成骨细胞前体的产生大幅减少以及成熟成骨细胞和骨细胞凋亡的增加这一假设，我们建议在长期糖皮质激素过量的小鼠模型中建立骨细胞祖细胞数量、组织形态和密度变化之间的时间关系。在小鼠和患者全股骨头标本中，我们将阐明糖皮质激素诱导成骨细胞和骨细胞凋亡的分子机制和程度，与治疗剂量和时间的相关性以及与骨坏死的关系。这一假设将通过使用(a)抗吸收剂阿仑膦酸钠对小鼠模型进行干预来进一步验证；(b) PTH，一种合成代谢和抗凋亡剂；(c)同时给予甲状旁腺激素和阿仑膦酸钠，以确定这些方案对维持成骨细胞数量和防止骨质流失的功效。

The adverse effects of hypercortisolism on bone have been recognized for over 60 years, but the precise cellular and molecular basis of these changes is still unclear and effective therapy has remained elusive. A cardinal feature of glucocorticoid-induced osteoporosis is decreased bone formation. In addition, patients receiving long-term glucocorticoid therapy sometimes develop collapse of the femoral head (osteonecrosis). Decreased bone formation and in situ death of isolated segments of the proximal femur suggest that glucocorticoid excess may alter the birth and death of bone cells. In preliminary studies leading to this application, it has been established that (1) the male Swiss Webster mouse is a valid and informative model of glucocorticoid-induced bone disease, not confounded by weight loss or sex-steroid deficiency, (2) many of the effects of chronic glucocorticoid administration on bone can be explained by decreased birth of osteoblast precursors and increased apoptosis of mature osteoblasts and osteocytes both in mice and in humans, and (3) decreased osteoblast apoptosis, rather than increased osteoblastogenesis, is the mechanism by which the intermittent administration of parathyroid hormone (PTH) stimulates bone formation - an effect that may be used to investigate the impact of glucocorticoid-induced apoptosis. To test the hypothesis that the adverse skeletal impact of glucocorticoid excess is due to a profound decrease in the birth of new osteoblast precursors in the bone marrow and an increase in apoptosis of mature osteoblasts and osteocytes, we propose to establish the temporal relationships between the changes in bone cell progenitor numbers, histomorphometry and densitometry in a murine model of long-term glucocorticoid excess. In the mouse and in archival specimens of whole femoral heads resected from patients, we will elucidate the molecular mechanisms and extent of glucocorticoid-induced apoptosis of osteoblasts and osteocytes, the correlation with the dose and duration of treatment and the relationship to osteonecrosis. The hypothesis will be further tested by intervention in the murine model with (a) alendronate, an antiresorptive agent; (b) PTH, an anabolic and anti-apoptotic agent; and (c) PTH and alendronate given concurrently to determine the efficacy of these regimens to maintain osteoblast numbers and prevent bone loss.