Mechanism of Bone Resorption in Periodontitis

牙周炎骨吸收机制

• 批准号: 10215661
• 负责人: Yasuyoshi Ueki
• 金额: $ 19.49万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215661
• 关键词: Adaptor Signaling Protein; Address; Adult; Affect; Alveolar Bone Loss; Bone Resorption; Cherubism; Child; Communicable Diseases; DNA Sequence Alteration; Data; Disease; Gene Mutation; Genetic Diseases; Gingiva; Goals; Health; Health Expenditures; Hereditary Disease; Human; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Knock-in Mouse; Knock-out; Knockout Mice; Lesion; Ligature; Malignant Neoplasms; Mandible; Maxilla; Mediator of activation protein; Molecular; Mus; Mutation; Myeloid Cells; Online Mendelian Inheritance In Man; Oral; Osteoclasts; Pathogenesis; Pathologic; Pathway interactions; Patients; Periodontal Diseases; Periodontitis; Pharmacotherapy; Phosphotransferases; Play; Pneumonia; Population; Predisposition; Production; Protein Binding Domain; Quality of life; Rare Diseases; Regulation; Rheumatoid Arthritis; Role; SH3 Domains; SYK gene; Severities; Signal Transduction; TLR2 gene; TNF gene; Testing; Therapeutic; Tissues; Tooth Loss; alveolar bone; base; bone; bone loss; cardiovascular disorder risk; craniofacial disorder; design; gain of function; gain of function mutation; gene discovery; inflammatory bone loss; inhibitor/antagonist; insight; loss of function; loss of function mutation; macrophage; mouse model; mutant; neutrophil; novel; oral bacteria; oral infection; osteoclastogenesis; pathogenic bacteria; public health relevance; rare condition; response

 DESCRIPTION (provided by applicant): Periodontitis is an oral inflammatory disease resulting in swollen gingiva and tooth loss due to resorption of alveolar bones, which reduce the quality of life. Over 47% of adult U.S. population has periodontitis. Periodontitis can also increase risk for cardiovascular disease and rheumatoid arthritis. Studies have suggested that a pathologic immune response to oral bacteria is primarily responsible for periodontitis and subsequent activation of osteoclasts, resulting in alveolar bone loss. However, the mechanisms of the induction of bone resorption in periodontitis are not fully understood. Therefore, the goal of this proposal is to identify and characterize the molecular and cellular mechanisms responsible for bone resorption in this poor condition. Our discovery of the gene mutations responsible for a rare craniofacial disorder "Cherubism" may provide novel insights into the mechanisms. Cherubism is a genetic disorder characterized by excessive destruction of mandibular and maxillary bones due to proliferation of inflammatory lesions containing a large number of osteoclasts. We have previously discovered that gain-of-function mutations in the signaling adaptor protein SH3-domain binding protein 2 (SH3BP2) are responsible for this rare condition. The mouse model of cherubism showed that the mutation increases responsiveness to bacterial pathogens and enhances tumor necrosis factor (TNF)-α production by macrophages. Hyper-activation of the toll-like receptor 2 and 4 by SYK kinase that interacts with mutant SH3BP2 is a major initiator of inflammation. Furthermore, we have discovered that gain- and loss-of-function of SH3BP2 respectively increases or decreases osteoclast formation in response to TNF-α. Recently, these studies have taken an exciting new direction based on our new discovery that SH3BP2 gain- and loss-of-function mutations have a profound effect on susceptibility to bone loss in a mouse model of periodontitis. This elevates the significance of SH3BP2 beyond its role in a rare inherited disorder and suggests that SH3BP2 is a critical player in inflammation and bone resorption in periodontitis. Therefore, our data have led us to a new hypothesis that SH3BP2 is responsible for the regulation of osteoclast activity during the progression of periodontitis resulting in alveolar bone loss. To test the hypothesis, the three specific aims are proposed: Aim 1) Determine the mechanism by which SH3BP2 gain-of-function increases bone loss in periodontitis. Aim 2) Determine the mechanism by which SH3BP2 loss- of-function protects against bone loss in periodontitis. Aim 3) Determine the effect of SYK inhibition on bone resorption in periodontitis. Completion of the proposed specific aims will further delineate the role of SH3BP2 as a key signaling mediator of inflammatory bone loss in periodontitis and will identify its downstream inflammatory mediators important for osteoclastogenesis. Confirmation that loss-of-function of SH3BP2 or inhibition of its downstream mediator SYK can protect against periodontitis-associated bone loss will open up new opportunities for targeting these pathways therapeutically for the treatment of periodontitis.

 牙周炎(申请人提供)：牙周炎是一种口腔炎症性疾病，因牙槽骨吸收而导致牙龈肿胀和牙齿脱落，从而降低生活质量。超过47%的美国成年人口患有牙周炎。牙周炎还会增加患心血管疾病和类风湿性关节炎的风险。研究表明，对口腔细菌的病理性免疫反应是牙周炎和随后的破骨细胞激活的主要原因，导致牙槽骨丢失。然而，在牙周炎中诱导骨吸收的机制还不完全清楚。因此，这项建议的目标是确定和表征在这种恶劣条件下导致骨吸收的分子和细胞机制。我们发现了导致一种罕见的头面部疾病“切尔贝氏症”的基因突变，这可能会为机制提供新的见解。切尔鲁比症是一种遗传性疾病，其特征是由于含有大量破骨细胞的炎性病变的增殖，导致下颌和上颌骨过度破坏。我们先前已经发现，信号转导蛋白SH3域结合蛋白2(SH3BP2)的功能获得突变是导致这种罕见疾病的原因。小鼠巨噬细胞缺乏症模型显示，该突变提高了对细菌病原体的反应性，并增强了巨噬细胞产生肿瘤坏死因子-α的能力。与突变型SH3BP2相互作用的SYK激酶过度激活Toll样受体2和4是炎症的主要启动者。此外，我们还发现SH3BP2的功能增强和功能丧失分别增加或减少了对肿瘤坏死因子-α的破骨细胞的形成。最近，基于我们的新发现，这些研究采取了一个令人兴奋的新方向，即SH3BP2功能获得和丧失突变对牙周炎小鼠模型骨丢失的易感性有深远影响。这使得SH3BP2的意义超越了它在一种罕见的遗传性疾病中的作用，并表明SH3BP2在牙周炎的炎症和骨吸收中起着关键作用。因此，我们的数据引导我们提出了一个新的假设，即SH3BP2在牙周炎发展过程中负责调节破骨细胞的活性，导致牙槽骨丢失。为了验证这一假设，提出了三个具体目标：目的1)确定SH3BP2功能获得增加牙周炎骨丢失的机制。目的2)探讨SH3BP2功能丧失对牙周炎骨丢失的保护作用机制。目的3)探讨抑制SYK对牙周炎患者骨吸收的影响。完成拟议的特定目标将进一步阐明SH3BP2作为牙周炎炎性骨丢失的关键信号介质的作用，并将确定其下游的炎性介质对破骨细胞的形成至关重要。证实SH3BP2功能丧失或抑制其下游介质SYK可以预防牙周炎相关的骨丢失，这将为针对这些途径治疗牙周炎打开新的机会。

项目成果

Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model.

第二代 SYK 抑制剂 Entospletinib 可改善 Cherubism 小鼠模型中完全建立的炎症和骨破坏。

• DOI: 10.1002/jbmr.3449
• 发表时间: 2018
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Yoshimoto,Tetsuya;Hayashi,Tatsuhide;Kondo,Toshio;Kittaka,Mizuho;Reichenberger,ErnstJ;Ueki,Yasuyoshi
• 通讯作者: Ueki,Yasuyoshi

Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice.

杂合子天使小鼠中微生物依赖性加剧的牙槽骨破坏。

• DOI: 10.1002/jbm4.10352
• 发表时间: 2020
• 期刊: JBMR plus
• 影响因子: 3.8
• 作者: Kittaka,Mizuho;Yoshimoto,Tetsuya;Schlosser,Collin;Kajiya,Mikihito;Kurihara,Hidemi;Reichenberger,ErnstJ;Ueki,Yasuyoshi
• 通讯作者: Ueki,Yasuyoshi

Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis.

• DOI: 10.1016/j.bone.2017.10.017
• 发表时间: 2018-01
• 期刊: Bone
• 影响因子: 4.1
• 作者: Fujita S;Mukai T;Mito T;Kodama S;Nagasu A;Kittaka M;Sone T;Ueki Y;Morita Y
• 通讯作者: Morita Y

Rescue of a cherubism bone marrow stromal culture phenotype by reducing TGFβ signaling.

通过减少 TGFβ 信号来拯救天使骨髓基质培养表型。

• DOI: 10.1016/j.bone.2018.03.009
• 发表时间: 2018
• 期刊: Bone
• 影响因子: 4.1
• 作者: Liu,Yaling;Sharma,Tulika;Chen,I-Ping;Reichenberger,Ernst;Ueki,Yasuyoshi;Arif,Yumna;Parisi,Daniel;Maye,Peter
• 通讯作者: Maye,Peter

RANKL-independent osteoclastogenesis in the SH3BP2 cherubism mice.

SH3BP2 天使小鼠中 RANKL 独立的破骨细胞生成。

• DOI: 10.1016/j.bonr.2020.100258
• 发表时间: 2020
• 期刊: Bone reports
• 影响因子: 2.5
• 作者: Kittaka,Mizuho;Yoshimoto,Tetsuya;Hoffman,Henry;Levitan,MarcusEvan;Ueki,Yasuyoshi
• 通讯作者: Ueki,Yasuyoshi