LACK OF CHANGE OF CANCELLOUS BONE VOLUME WITH SHORT-TERM USE OF THE NEW IMMUNOSUPPRESSANT RAPAMYCIN IN RATS
LACK OF CHANGE OF CANCELLOUS BONE VOLUME WITH SHORT-TERM USE OF THE NEW IMMUNOSUPPRESSANT RAPAMYCIN IN RATS
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DOI：
10.1007/bf01352014
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发表时间：
1993-07-01
影响因子：
4.2
通讯作者：
EPSTEIN, S
中科院分区：
文献类型：
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作者：
JOFFE, I;KATZ, I;EPSTEIN, S
在动物和人体研究中，免疫抑制剂对骨矿物质代谢有不良影响，皮质类固醇产生低转换骨量减少，环孢素A（CsA）产生高转换骨量减少。雷帕霉素（Rapamycin，RAPA）是一种新型免疫抑制剂，其作用至少是CsA的10倍，并且通过与CsA和另一种新型免疫抑制剂FK 506不同的途径起作用。本研究探讨了RAPA对大鼠骨矿物质代谢的影响。将42只10周龄的雄性Sprague道利大鼠分成三组，并根据以下方案进行处理：A组（对照）通过每天管饲法接受RAPA载体，持续14天（n = 12）; B组（对照）通过每天管饲法接受RAPA载体，持续14天（n = 12）。（高剂量RAPA组）15只，每天灌胃RAPA 2.5mg/kg/d，共14天; C组（低剂量RAPA组）15只，每天灌胃RAPA 1.25mg/kg，连续14 d。分别于第0、7、14天流血的，测定血清游离钙、骨钙素（BGP）、甲状旁腺素（PTH）和1，25（OH）2D。双钙黄绿素标记后第14天测定胫骨骨组织形态计量学。与对照动物相比，RAPA治疗的两组动物的体重增加相似。高剂量RAPA（组B）在第7天暂时降低血清BGP水平，在第7天升高血液离子钙水平，并且在第14天降低1，25（OH）2D水平。血清PTH水平无变化。低剂量RAPA（C组）不影响促钙激素。胫骨干骺端的组织形态学分析显示，与对照动物（A组）相比，RAPA治疗组（B和C组）的骨形成和骨吸收参数无显著差异。与A组（对照组）（16.42 +/- 0.86%）相比，B组（高剂量RAPA）（15.39 +/- 1.01%）和C组（低剂量RAPA）（15.38 +/- 0.57%）的小梁骨体积（BV/TV）没有显著改变。与CsA不同，RAPA短期治疗不会导致过度吸收和骨量丢失。高剂量RAPA治疗后血清1，25（OH）2D水平降低，可能对骨矿物质代谢产生长期不利影响。
Immunosuppressants have adverse effects on bone mineral metabolism in animal and human studies, with corticosteroids producing low-turnover osteopenia, and cyclosporin-A (CsA) producing high-turnover osteopenia. Rapamycin (RAPA) is a new immunosuppressant reported to be at least 10 times more potent than CsA, and acts via a different pathway to CsA and the other new immunosuppressant FK506. This study investigated the effects of RAPA on bone mineral metabolism in the rat. Forty-two, 10-week-old, male Sprague Dawley rats were divided into three groups, and treated according to the following protocol: group A (control) received RAPA vehicle by daily gavage for 14 days (n = 12); group B (high dose RAPA) received RAPA 2.5 mg/kg/day by daily gavage for 14 days (n = 15); group C (low dose RAPA) received RAPA 1.25 mg/kg/day by daily gavage for 14 days (n = 15). Rats were weighed and bled on days 0, 7, and 14 for measurement of blood ionized calcium, bone Gla protein (BGP), parathyroid hormone (PTH), and 1,25(OH)2D. Tibial bone histomorphometry was determined on day 14 after double-calcein labeling. Weight gain was similar in the two groups treated with RAPA compared with control animals. High-dose RAPA (group B) transiently depressed serum BGP levels on day 7, with elevated blood ionized calcium levels on day 7, and lowered 1,25(OH)2D levels on day 14. Serum PTH levels were unchanged. Low-dose RAPA (group C) did not affect calciotropic hormones. Histomorphometric analyses of tibial metaphyses revealed that parameters of bone formation and resorption were not significantly different in the groups treated with RAPA (group B and C) compared with control animals (group A). Trabecular bone volume (BV/TV) in group B (high-dose RAPA) (15.39 +/- 1.01%) and C (low-dose RAPA) (15.38 +/- 0.57%) was not significantly altered compared with group A (control) (16.42 +/- 0.86%). Short-term treatment with RAPA, unlike CsA, does not result in excess resorption and loss of bone volume. The depressed serum 1,25(OH)2D levels seen with high-dose RAPA therapy may adversely effect bone mineral metabolism in the long term.