Abstract
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.
Highlights
This article is an open access articlePeriodontal disease is characterized by gingival inflammation with subsequent destruction of tooth-supporting soft and hard tissues [1,2]
These results indicate that platelets release both soluble Sema4D (sSema4D) and IGF-1 in the culture supernatant, whereas thrombin-mediated activation of platelets promotes the release of sSema4D, but not IGF-1
Actb was used as an internal reference control. (Figure 3D). These results suggest that Semaphorin 4D (Sema4D) released from thrombinactivated platelets (TPs) attenuated osteoblastogenesis through suppression of an IGF-1-elicited cell signal involving the Akt and ERK pathway, which plays a pivotal role in promoting osteoblast differentiation and bone formation [29,30]
Summary
Periodontal disease is characterized by gingival inflammation with subsequent destruction of tooth-supporting soft and hard tissues [1,2] It is well-documented that bone regeneration hardly ever occurs at the alveolar bone affected by periodontitis [3,4]. A variety of approaches have been developed to regenerate tooth-supporting tissues, including periodontal ligament, cementum and alveolar bone [5–8]. One of these distributed under the terms and conditions of the Creative Commons. Platelets are known to be a rich source of many growth factors, such as platelet-derived growth factor, IGF-1 and TGF-β [8,10] For this reason, platelets have been used for the regeneration of connective tissue, epithelium and tendon in orthopedic and periodontal therapies [11,12]. Irrespective of the presence of robust bone regenerative factors in platelets, other studies demonstrated a lack of or limited efficacy of PRP in improving bone formation at the bone loss site in periodontitis, as well as bone defect in other oral maxillofacial pathology [15–21]
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