A mouse model for glucocorticoid-induced osteonecrosis: effect of a steroid holiday.
A mouse model for glucocorticoid-induced osteonecrosis: effect of a steroid holiday.
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DOI：
10.1002/jor.20733
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发表时间：
2009-02
影响因子：
2.8
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
--
作者：
Yang, Lei;Boyd, Kelli;Kaste, Sue C.;Kamdem, Landry Kamdem;Rahija, Richard J.;Relling, Mary V.
糖皮质激素诱导的骨坏死是一种常见的剂量限制性不良事件。本研究的目的是建立一种糖皮质激素诱导的骨坏死的小鼠模型，以测试不同的治疗策略对其频率的影响。使用各种糖皮质激素、给药途径和饮食筛选了14种鼠品系。在有或没有天冬酰胺酶的情况下，通过连续给药或不连续给药，用口服地塞米松处理4周龄雄性BALB/cJ小鼠长达12周。光镜下观察股骨远端的组织学特征。骨坏死病变的特点是骨小梁内空陷窝和骨细胞影，周围有坏死的骨髓和水肿。12周时，BALB/cJ小鼠地塞米松诱导的骨坏死发生率为40%-45%（4/10或5/11）。尽管累积血浆暴露量相当，但与连续给药12周相比，间断给药后骨坏死的频率趋势较低（8% vs 45%）（P = 0.06）。门冬酰胺酶可加速骨坏死的发生，早在4周时就已观察到，6周后发生率为50%。建立糖皮质激素诱导的小鼠骨坏死模型。间断地塞米松治疗的骨坏死比连续地塞米松治疗少，这与临床环境中观察到的“类固醇假期”的可能益处一致。此外，天冬酰胺酶加速骨坏死，表明药物可能与糖皮质激素相互作用，影响骨坏死的风险。
Glucocorticoid-induced osteonecrosis is a common and dose-limiting adverse event. The goal of this study was to establish a mouse model of glucocorticoid-induced osteonecrosis suitable for testing the effects of different treatment strategies on its frequency. Fourteen murine strains were screened using various glucocorticoids, routes of administration, and diets. Four-week old male BALB/cJ mice were treated with oral dexamethasone for up to 12 weeks either by continuous dosing or by discontinuous dosing, with or without asparaginase. Histopathological features of the distal femurs were examined by light microscopy. Osteonecrotic lesions were characterized by empty lacunae and osteocyte ghosts in trabecular bone surrounded by necrotic marrow and edema. The incidence of dexamethasone induced osteonecrosis in BALB/cJ mice was 40%–45% (4/10 or 5/11) at 12 weeks. The frequency of osteonecrosis trended lower after discontinuous compared to continuous dosing for 12 weeks (8% vs. 45%) (P = 0.06) despite comparable cumulative plasma exposure. Asparaginase hastened the occurrence of osteonecrosis which was observed as early as 4 weeks and the incidence was 50% after 6 weeks. A mouse model of glucocorticoid-induced osteonecrosis was established. Discontinuous was less osteonecrotic than continuous dexamethasone treatment, consistent with the possible benefits of a “steroid holiday” seen in clinical settings. Moreover, asparaginase hastened osteonecrosis, indicating that drugs may interact with glucocorticoids to affect osteonecrosis risk.
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影响因子：
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通讯作者：
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