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首页> 外文期刊>FEBS Open Bio >A small‐molecule PAI‐1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency‐induced osteoporosis model
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A small‐molecule PAI‐1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency‐induced osteoporosis model

机译：在鼠雌激素缺乏引起的骨质疏松症模型中，一种小分子PAI-1抑制剂可通过刺激骨形成来防止骨质流失

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Osteoporosis is a progressive bone disease caused by an imbalance between bone resorption and formation. Recently, plasminogen activator inhibitor‐1 (PAI‐1) was shown to play an important role in bone metabolism using PAI‐1‐deficient mice. In this study, we evaluated the therapeutic benefits of novel, orally available small‐molecule PAI‐1 inhibitor (iPAI‐1) in an estrogen deficiency‐induced osteoporosis model. Eight‐week‐old C57BL/6J female mice were divided into three groups: a sham + vehicle (Sham), ovariectomy + vehicle (OVX + v), and OVX + iPAI‐1 (OVX + i) group. iPAI‐1 was administered orally each day for 6 weeks starting the day after the operation. Six weeks of iPAI‐1 treatment prevented OVX‐induced trabecular bone loss in both the femoral bone and lumbar spine. Bone formation activity was significantly higher in the OVX + i group than in the OVX + v and Sham groups. Unexpectedly, OVX‐induced osteoclastogenesis was partially, but significantly reduced. Fluorescence‐activated cell sorting analyses indicated that the number of bone marrow stromal cells was higher in the OVX + i group than that in the OVX + v group. A colony‐forming unit‐osteoblast assay indicated enhanced mineralized nodule formation activity in bone marrow cells isolated from iPAI‐1‐treated animals. Bone marrow ablation analysis indicated that the remodeled trabecular bone volume was significantly higher in the iPAI‐1‐treated group than that in the control group. In conclusion, our results suggest PAI‐1 blockade via a small‐molecule inhibitor is a new therapeutic approach for the anabolic treatment of postmenopausal osteoporosis.
机译：骨质疏松症是一种由于骨骼吸收和形成之间的不平衡而引起的进行性骨骼疾病。最近，已证明纤溶酶原激活物抑制剂-1（PAI-1）在使用PAI-1缺陷小鼠的骨代谢中起重要作用。在这项研究中，我们评估了新型的口服小分子PAI-1抑制剂（iPAI-1）在雌激素缺乏引起的骨质疏松症模型中的治疗效果。将八周大的C57BL / 6J雌性小鼠分为三组：假手术+媒介物（Sham），卵巢切除术+媒介物（OVX + v）和OVX + iPAI-1（OVX + i）组。从术后第二天开始，每天口服iPAI-1，持续6周。 iPAI-1治疗六周预防了股骨和腰椎OVX引起的小梁骨丢失。 OVX + i组的骨形成活性明显高于OVX + v和Sham组。出乎意料的是，OVX诱导的破骨细胞发生了部分，但明显减少。荧光激活细胞分选分析表明，OVX + i组的骨髓基质细胞数量高于OVX + v组。菌落形成单位成骨细胞试验表明，从经过iPAI-1处理的动物中分离出的骨髓细胞中矿化的结节形成活性增强。骨髓消融分析表明，iPAI-1治疗组的重塑小梁骨体积明显高于对照组。总之，我们的结果表明，通过小分子抑制剂阻断PAI-1是一种绝经后骨质疏松的合成代谢治疗的新治疗方法。

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