A small‐molecule PAI‐1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency‐induced osteoporosis model
| Autor: | Tetsuo Nakabayashi, Guangwen Jin, Shingo Sato, Zulipiya Aibibula, Jinying Piao, Kunikazu Tsuji, Daisuke Koga, Toshio Miyata, Hiroki Ochi, Alkebaier Aobulikasimu, Atsushi Okawa, Yoshinori Asou |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Stromal cell Bone disease Osteoporosis General Biochemistry Genetics and Molecular Biology Bone resorption Bone remodeling 03 medical and health sciences chemistry.chemical_compound Bone Marrow Ablation Internal medicine medicine Research Articles bone formation medicine.disease osteoporosis postmenopause 030104 developmental biology medicine.anatomical_structure Endocrinology ovariectomy chemistry Plasminogen activator inhibitor-1 plasminogen activator inhibitor‐1 Bone marrow Research Article |
| Zdroj: | FEBS Open Bio |
| ISSN: | 2211-5463 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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