Role of platelets in periodontal bone remodeling.

摘要 这项R15拨款提案旨在研究血小板在牙周炎中可能的致病作用。 牙周炎是一种以宿主免疫性炎症为特征的口腔多菌感染性疾病。 对牙周细菌的反应，导致骨骼和结缔组织的破坏。虽然很多人 在牙周免疫病理中对免疫细胞和免疫成分的多样性进行了研究，仅有少数研究 报道了牙周炎病变中活化的血小板募集增加。尽管血小板被激活 凝血酶和/或内毒素在感染诱导的组织损伤中发挥关键的宿主保护作用 通过产生多种生长因子诱导组织再生，包括血管内皮生长因子、PDGF、转化生长因子-β和 IGF-1，血小板在牙周炎中可能的病理生理作用在很大程度上是未知的。最新研究 据报道，活化的血小板与类风湿性关节炎的发病机制有关。 动脉粥样硬化，而不是引发宿主保护作用。 而富含血小板血浆(PRP)能有效地诱导大鼠软组织再生。 牙周组织、PRP治疗牙周炎所致牙槽骨缺损效果不一致 导致“新骨形成”的诱导。这一现象表明，存在着一些未知的 血小板中的分子抑制骨生长因子如转化生长因子-β和胰岛素样生长因子-1诱导的骨再生。 为此，我们针对最近发现的抗骨生成分子Semaphorin 4D(Sema4D)，a IGF-1介导的成骨细胞生成的负调控因子(OB-Genesis)。据报道，活化的血小板 TACE(ADAM-17)介导的释放功能活性的可溶性Sema4D(SSema4D) 膜结合形式的Sema4D。理论上，与功能成熟所需的肿瘤坏死因子-a类似 TACE介导的脱落从其膜结合形式，TACE介导的脱落可能在 函数式sSema4D的生成。 在提议的项目中，我们假设由血小板产生的Sema4D不仅抑制OB- Genesis，但也促进病理性破骨细胞生成(OC-Genesis)。我们进一步建立了一个分部- 病原体相关分子模式(PAMP)，特别是内毒素，由牙周产生的假说 细菌参与促进血小板产生sSema4D。 本研究将1)确定血小板在炎症性骨病中的病理生理学作用 牙周炎的吸收损害，2)阐明抑制血小板介导骨的分子机制 牙周炎的再生，并基于从1)和2)获得的见解，3)开发一种新的方法来 提高血小板介导骨再生疗法在牙周炎中的应用效果。这项建议 代表着牙周炎和牙周炎新的再生疗法发展中潜在的范式转变 其他骨溶解疾病。

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.