A small-molecule PAI-1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency-induced osteoporosis model

作者：Jin, Guangwen; Aobulikasimu, Alkebaier; Piao, Jinying; Aibibula, Zulipiya; Koga, Daisuke; Sato, Shingo; Ochi, Hiroki; Tsuji, Kunikazu; Nakabayashi, Tetsuo; Miyata, Toshio; Okawa, Atsushi; Asou, Yoshinori^*

来源：FEBS Open Bio, 2018, 8(4): 523-532.

DOI：10.1002/2211-5463.12390

• bone formation
• osteoporosis
• ovariectomy
• plasminogen activator inhibitor-1
• postmenopause

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 6weeks 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.

• 出版日期2018-4
• 单位延边大学