Locally Secreted Semaphorin 4D Is Engaged in Both Pathogenic Bone Resorption and Retarded Bone Regeneration in a Ligature-Induced Mouse Model of Periodontitis

Takenobu Ishii, Montserrat Ruiz-Torruella, Kenta Yamamoto, Tsuguno Yamaguchi, Alireza Heidari, Roodelyne Pierrelus, Elizabeth Leon, Satoru Shindo, Mohamad Rawas-Qalaji, Maria Rita Pastore, Atsushi Ikeda, Shin Nakamura, Hani Mawardi, Umadevi Kandalam, Patrick Hardigan, Lukasz Witek, Paulo G. Coelho, Toshihisa Kawai

Research output: Contribution to journalArticlepeer-review


It is well known that Semaphorin 4D (Sema4D) inhibits IGF-1-mediated osteogenesis by binding with PlexinB1 expressed on osteoblasts. However, its elevated level in the gingival crevice fluid of periodontitis patients and the broader scope of its activities in the context of potential upregulation of osteoclast-mediated periodontal bone-resorption suggest the need for further investigation of this multifaceted molecule. In short, the pathophysiological role of Sema4D in periodontitis requires further study. Accordingly, attachment of the ligature to the maxillary molar of mice for 7 days induced alveolar bone-resorption accompanied by locally elevated, soluble Sema4D (sSema4D), TNF-α and RANKL. Removal of the ligature induced spontaneous bone regeneration during the following 14 days, which was significantly promoted by anti-Sema4D-mAb administration. Anti-Sema4D-mAb was also suppressed in vitro osteoclastogenesis and pit formation by RANKL-stimulated BMMCs. While anti-Sema4D-mAb downmodulated the bone-resorption induced in mouse periodontitis, it neither affected local production of TNF-α and RANKL nor systemic skeletal bone remodeling. RANKL-induced osteoclastogenesis and resorptive activity were also suppressed by blocking of CD72, but not Plexin B2, suggesting that sSema4D released by osteoclasts promotes osteoclastogenesis via ligation to CD72 receptor. Overall, our data indicated that ssSema4D released by osteoclasts may play a dual function by decreasing bone formation, while upregulating bone-resorption.

Original languageEnglish (US)
Article number5630
JournalInternational journal of molecular sciences
Issue number10
StatePublished - May 1 2022


  • Semaphorin 4D
  • bone regeneration
  • osteoblasts
  • osteoclasts
  • periodontitis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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