INTERLEUKIN-1 RECEPTOR ANTAGONIST DECREASES BONE LOSS AND BONE-RESORPTION IN OVARIECTOMIZED RATS
INTERLEUKIN-1 RECEPTOR ANTAGONIST DECREASES BONE LOSS AND BONE-RESORPTION IN OVARIECTOMIZED RATS
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DOI：
10.1172/jci117187
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发表时间：
1994-05-01
影响因子：
15.9
通讯作者：
PACIFICI, R
中科院分区：
文献类型：
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作者：
KIMBLE, RB;VANNICE, JL;PACIFICI, R
白细胞介素1(IL-1)是一种由骨髓细胞和骨细胞产生的细胞因子，在体内和体外均能促进骨吸收，与绝经后骨质疏松症的发病机制密切相关。为探讨IL-1是否在卵巢切除后骨质丢失中起直接作用，对6个月龄去卵巢大鼠皮下注射IL-1受体拮抗剂IL-1ra(IL-1受体拮抗剂)4wk，分别从手术时或术后4wk开始。采用双能X线骨密度仪无创性测量股骨远端骨密度。通过骨组织形态计量学和测量血清骨钙素(骨形成的标志)和尿吡啶交联物的排泄量(骨吸收的标志)来评估骨转换。卵巢切除导致骨转换迅速增加，骨密度显著降低，而17β雌二醇可阻断这一过程。卵巢切除也增加了培养的骨髓细胞产生的IL-1。IL-1ra可显著减少去卵巢时的骨丢失，而在去卵巢后4wk开始完全阻断IL-1ra。在这两项研究中，IL-1ra也以类似雌激素的方式减少骨吸收，但对骨形成没有影响。相反，IL-1ra治疗对假手术大鼠的骨密度和骨转换无影响，表明IL-1ra特异性地阻断雌激素依赖性的骨丢失。综上所述，这些数据表明，IL-1或由IL-1诱导的介质在卵巢切除导致大鼠骨质丢失的机制中起着重要的因果作用，尤其是在卵巢切除后即刻。
Interleukin-1 (IL-1), a cytokine produced by bone marrow cells and bone cells, has been implicated in the pathogenesis of postmenopausal osteoporosis because of its potent stimulatory effects on bone resorption in vitro and in vivo. To investigate whether IL-1 plays a direct causal role in post ovariectomy bone loss, 6-mo-old ovariectomized rats were treated with subcutaneous infusions of IL-1 receptor antagonist (IL-1ra), a specific competitor of IL-1, for 4 wk, beginning either at the time of surgery or 4 wk after ovariectomy. The bone density of the distal femur was measured non invasively by dual-energy X-ray absorptiometry. Bone turnover was assessed by bone histomorphometry and by measuring serum osteocalcin, a marker of bone formation, and the urinary excretion of pyridinoline crosslinks, a marker of bone resorption. Ovariectomy caused a rapid increase in bone turnover and a marked decrease in bone density which were blocked by treatment with 17 beta estradiol. Ovariectomy also increased the production of IL-1 from cultured bone marrow cells. Ovariectomy induced bone loss was significantly decreased by IL-1ra treatment started at the time of ovariectomy and completely blocked by IL-1ra treatment begun 4 wk after ovariectomy. In both studies IL-1ra also decreased bone resorption in a manner similar to estrogen, while it had no effect on bone formation. In contrast, treatment with IL-1ra had no effect on the bone density and the bone turnover of sham-operated rats, indicating that IL-1ra specifically blocked estrogen-dependent bone loss. In conclusion, these data indicate that IL-1, or mediators induced by IL-1, play an important causal role in the mechanism by which ovariectomy induces bone loss in rats, especially following the immediate post ovariectomy period.