Abstract
This R15 grant proposal aims to study the possible pathogenic roles of platelets in periodontitis.
Periodontitis, an oral polymicrobial infectious disease, is characterized by host immune-inflammatory
responses to periodontal bacteria, leading to the destruction of bone and connective tissues. While many
varieties of immune cells and components were studied in periodontal immunopathology, only a few studies
reported the elevated recruitment of activated platelets in periodontitis lesion. Although platelets activated by
thrombin and/or LPS play key host-protective roles in infection-induced tissue damage by thrombosis and
induction of tissue regeneration by production of variety of growth factors, including, VEGF, PDGF, TGF-b and
IGF-1, the possible pathophysiological role of platelets in periodontitis is largely unknown. Recent studies
reported that the activated platelets are associated with pathogenesis of Rheumatoid arthritis and
atherosclerosis, instead of eliciting host protective effects.
While platelet-enriched plasma (PRP) is effective in induction of “soft tissue regeneration” in
periodontium, PRP therapy applied to the alveolar bone defect caused by periodontitis shows inconsistent
results in induction of “new bone formation.” This phenomenon indicates that the presence of some unknown
molecules in platelets inhibits bone regeneration induced by bone growth factors, such as, TGF-b and IGF-1.
To this end, we have targeted recently identified anti-osteogenic molecule, Semaphorin 4D (Sema4D), a
negative regulator of IGF-1-mediated osteoblastogenesis (OB-genesis). It was reported that activated platelets
release functionally active soluble Sema4D (sSema4D) because of TACE (ADAM-17) mediated shedding of
membrane bound form of Sema4D. It is theorized that, similar to TNF-a of which functional maturation requires
TACE-mediated shedding from its membrane bound form, TACE-mediated shedding may play a key role in
generation of functional sSema4D.
In the proposed project, we hypothesized that Sema4D produced by platelets not only suppresses OB-
genesis, but also promotes pathogenic osteoclastogenesis (OC-genesis). We further established a sub-
hypothesis that pathogen associated molecular patterns (PAMPs), in particular LPS, produced by periodontal
bacteria are engaged in promoting the generation of sSema4D from platelets.
This study will 1) establish the pathophysiological role of platelets in the context of inflammatory bone
resorption lesion of periodontitis, 2) elucidate the molecular mechanism that arrests platelet-mediated bone
regeneration in periodontitis, and, based on insights gained from 1) and 2), 3) develop a new approach to
improve the effects of platelet-mediated bone regenerative therapy applied to periodontitis. This proposal
represents a potential paradigm shift in the development of novel regenerative therapies for periodontitis and
other bone lytic diseases.