Dual-Function Semaphorin 4D Released by Platelets: Promotion of Suppression of Osteoblastogenesis and Osteoclastogenesis

Satoru Shindo, Irma Josefina Savitri, Takenobu Ishii, Atsushi Ikeda, Roodelyne Pierrelus, Alireza Heidari, Keisuke Okubo, Shin Nakamura, Umadevi Kandalam, Mohamad Rawas-Qalaji, Elizabeth Leon, Maria Rita Pastore, Patrick Hardigan, Toshihisa Kawai

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9 Citations (Scopus)


Effects of the antiosteoblastogenesis factor Semaphorin 4D (Sema4D), expressed by thrombin-activated platelets (TPs), on osteoblastogenesis, as well as osteoclastogenesis, were investigated in vitro. Intact platelets released both Sema4D and IGF-1. However, in response to stimulation with thrombin, platelets upregulated the release of Sema4D, but not IGF-1. Anti-Sema4D-neutralizing monoclonal antibody (mAb) upregulated TP-mediated osteoblastogenesis in MC3T3-E1 osteoblast precursors. MC3T3-E1 cells exposed to TPs induced phosphorylation of Akt and ERK further upregulated by the addition of anti-sema4D-mAb, suggesting the suppressive effects of TP-expressing Sema4D on osteoblastogenesis. On the other hand, TPs promoted RANKL-mediated osteoclastogenesis in the primary culture of bone-marrow-derived mononuclear cells (BMMCs). Among the known three receptors of Sema4D, including Plexin B1, Plexin B2 and CD72, little Plexin B2 was detected, and no Plexin B1 was detected, but a high level of CD72 mRNA was detected in RANKL-stimulated BMMCs by qPCR. Both anti-Sema4D-mAb and anti-CD72-mAb suppressed RANKL-induced osteoclast formation and bone resorptive activity, suggesting that Sema4D released by TPs promotes osteoclastogenesis via ligation to a CD72 receptor. This study demonstrated that Sema4D released by TPs suppresses osteogenic activity and promotes osteoclastogenesis, suggesting the novel property of platelets in bone-remodeling processes.

Original languageEnglish
Article number2938
JournalInternational Journal of Molecular Sciences
Issue number6
Publication statusPublished - 1 Mar 2022


  • Bone regeneration
  • Osteoblasts
  • Osteoclasts
  • Platelets
  • Semaphorin 4D


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