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

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

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3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)523-532
Number of pages10
JournalFEBS Open Bio
Volume8
Issue number4
DOIs
Publication statusPublished - 2018 Apr

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Jin, G., Aobulikasimu, A., Piao, J., Aibibula, Z., Koga, D., Sato, S., Ochi, H., Tsuji, K., Nakabayashi, T., Miyata, T., Okawa, A., & Asou, Y. (2018). A small-molecule PAI-1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency-induced osteoporosis model. FEBS Open Bio, 8(4), 523-532. https://doi.org/10.1002/2211-5463.12390