Mann G N, Sass D A, Chen H K, Buchinsky F J, Bryer H P, Ma Y F, Jee W S, Rucinski B, Epstein S
Division of Endocrinology and Metabolism, Department of Medicine, Albert Einstein Medical Center, 5401 Old York Rd., Philadelphia, Pennsylvania 19141, USA.
Calcif Tissue Int. 1996 Jul;59(1):38-44. doi: 10.1007/s002239900083.
Immunosuppression with cyclosporin A (CsA) is effective in a number of immune-mediated diseases and in preventing rejection following organ transplantation. We have repeatedly demonstrated that CsA in the rat model produces accelerated bone remodelling with net bone loss, best characterized in trabecular bone. IGF-I holds promise as a treatment for various osteopenic conditions. Although currently a subject of much controversy, various studies have suggested that in vivo it is anabolic to cortical as well as trabecular bone. The purpose of this study was, in part, to further characterize the effects of CsA and IGF-I on trabecular and cortical bone, and to see whether systemic IGF-I is able to modulate CsA's deleterious skeletal effects. Sixty 10 week-old, male, Sprague-Dawley rats were randomized to receive the following daily for 3 weeks: (1) CsA vehicle (veh) per os (po) + recombinant human (rh) IGF-1 veh subcutaneously (sc); (2) CsA 15 mg/kg po + rhIGF-I-veh; (3) CsA-veh + rhIGF-I 200 microg/kg sc; (4) CsA-veh + rhIGF-I 600 microg/kg sc; (5) CsA 15 mg/kg + rhIGF-I 200 microg/kg, and (6) CsA 15 mg/kg + rhIGF-I 600 microg/kg. Rats were weighed and venous blood was sampled serially for determination of glucose, ionized calcium (Ca2+), PTH, vitamin D, and osteocalcin. Following sacrifice on day 20, histomorphometry was performed on double calcein-labeled tibial metaphysis and diaphysis. All rats receiving CsA had elevated levels of blood glucose and osteocalcin by day 9 and vitamin D at day 20. PTH was similar in all groups, and Ca2+ was only raised in the CsA and CsA + IGF-I 200 microg/kg groups. Rats receiving IGF-I 200 microg/kg and IGF-I 600 microg/kg gained more weight than either vehicle- or CsA-treated animals, attesting to IGF-1's anabolic properties. CsA caused severe trabecular bone loss, not prevented by IGF-I; it even further increased the eroded surface. CsA and IGF-I had little effect on cortical bone volume or marrow area. IGF-I increased endocortical matrix synthesis, as evidenced by the increases in the percent endocortical osteoid perimeter, an effect negated by the addition of CsA. This experiment demonstrates that trabecular bone is more susceptible than cortical bone to the deleterious effects of CsA and indicates little role for IGF-1 in the pathophysiology or treatment of CsA-induced bone disease at the given doses and duration of treatment.
用环孢素A（CsA）进行免疫抑制在多种免疫介导的疾病以及预防器官移植后的排斥反应方面是有效的。我们已经反复证明，在大鼠模型中，CsA会导致骨重塑加速并伴有净骨量丢失，这在小梁骨中表现最为明显。胰岛素样生长因子-I（IGF-I）有望用于治疗各种骨质减少病症。尽管目前存在诸多争议，但各种研究表明，在体内它对皮质骨和小梁骨都具有合成代谢作用。本研究的部分目的是进一步明确CsA和IGF-I对小梁骨和皮质骨的影响，并观察全身性IGF-I是否能够调节CsA对骨骼的有害作用。将60只10周龄的雄性Sprague-Dawley大鼠随机分组，连续3天每日接受以下处理：（1）口服CsA溶媒（veh）+皮下注射重组人（rh）IGF-1溶媒；（2）口服15 mg/kg CsA + rhIGF-I溶媒；（3）口服CsA溶媒+皮下注射200 μg/kg rhIGF-I；（4）口服CsA溶媒+皮下注射600 μg/kg rhIGF-I；（5）口服15 mg/kg CsA +皮下注射200 μg/kg rhIGF-I；（6）口服15 mg/kg CsA +皮下注射600 μg/kg rhIGF-I。对大鼠进行称重，并连续采集静脉血以测定血糖、离子钙（Ca2+）、甲状旁腺激素（PTH）、维生素D和骨钙素。在第20天处死大鼠后，对用双荧光素标记的胫骨近端干骺端和骨干进行组织形态计量学分析。到第9天时，所有接受CsA的大鼠血糖和骨钙素水平升高，到第20天时维生素D水平升高。所有组的PTH相似，仅CsA组和CsA + 200 μg/kg IGF-I组的Ca2+升高。接受200 μg/kg IGF-I和600 μg/kg IGF-I的大鼠比接受溶媒或CsA处理的动物体重增加更多，证明了IGF-1的合成代谢特性。CsA导致严重的小梁骨丢失，IGF-I无法预防；它甚至进一步增加了侵蚀表面。CsA和IGF-I对皮质骨体积或骨髓面积影响很小。IGF-I增加了皮质内基质合成，这表现为皮质内类骨质周长百分比增加，而添加CsA会抵消这种作用。本实验表明，小梁骨比皮质骨更容易受到CsA的有害影响，并且在给定的剂量和治疗持续时间下，IGF-1在CsA诱导的骨病的病理生理学或治疗中作用不大。
