Molecular and Cellular Pathogenesis of Cherubism

Cherubism 的分子和细胞发病机制

• 批准号: 8608941
• 负责人: Yasuyoshi Ueki
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608941
• 关键词: Adaptor Signaling Protein; Address; Affect; B-Lymphocytes; Back; Binding Proteins; Bone Diseases; Bone Resorption; Cell Lineage; Cherubism; Data; Development; Disease; Exhibits; Face; Genes; Genetic; Genetic Transcription; Goals; Hereditary Disease; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-1; Investigation; Jaw; Joints; Knock-in Mouse; Knockout Mice; Lesion; Ligands; MAPK3 gene; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Mediating; Missense Mutation; Modeling; Molecular; Molecular Analysis; Mus; Mutation; Myelogenous; Myeloid Cells; Names; Nuclear; Oral cavity; Osteoclasts; PTPN6 gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Periodontal Diseases; Pharmaceutical Preparations; Play; Production; Receptor Signaling; Rest; Rheumatoid Arthritis; Role; SH3 Domains; Serum; Signal Pathway; Signal Transduction; Site; Skeleton; Swelling; TNF gene; TNFSF11 gene; Testing; Therapeutic Intervention; Tissues; Tumor Necrosis Factor-alpha; bone; bone loss; cytokine; design; disease-causing mutation; feeding; human disease; in vitro Assay; in vivo; insight; macrophage; microbial; mouse model; mutant; novel; osteoclastogenesis; pathogen; public health relevance; receptor; response; skeletal

DESCRIPTION (provided by applicant): "Cherubism" is a human autosomal dominant disorder characterized by excessive bone resorption and the accumulation of inflammatory fibrous tissue in the jaws. We identified the gene responsible for this human disease, a signaling adaptor protein called "SH3 domain binding protein 2 (SH3BP2)", and pinpointed the mutations responsible for this condition. To further investigate the pathogenesis of Cherubism, we have generated a knock-in mouse model carrying this mutation (P416R in mice). Similar to the human disease, the cherubism mice exhibit systemic macrophage-driven inflammation with increased tumor necrosis factor-alpha (TNF-1) production as well as enhanced osteoclast differentiation, resulting in severe systemic inflammatory bone loss. Therefore these mice are useful, not only as a model of cherubism, but also potentially as a model for other inflammatory bone diseases. The overall hypothesis for the proposed studies is that the misexpression and disregulation of TNF-1 in Cherubism-associated inflammatory bone disease is mediated through SH3BP2 signaling in myeloid lineage cells. We propose SH3BP2 mutations result in abnormal signaling in macrophages and osteoclast precursors in response to macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-KB (NF-KB) ligand (RANKL), respectively. We also propose that the hyperactive macrophages are responsible for elevated TNF-1 which can feed back to further activate the osteoclasts, already made hyperactive through mutant SH3BP2. Our preliminary data suggest that ERK and MyD88 are involved in TNF- 1 production by hyperactive macrophages, while Syk and NFATc1 are involved in osteoclast hyperactivation. To test these hypotheses, the following specific aims are proposed: 1) Determine the mechanisms by which SH3BP2 regulates TNF-1 production in macrophages, 2) Determine the role of SH3BP2 in NFATc1-mediated osteoclast differentiation, and 3) Determine the role of the MyD88-mediated signaling pathway in the pathogenesis of inflammation in cherubism. The cherubism mouse model will be crossed with other mouse models such as the SHP-1 and MyD88 null mice in conjunction with relevant in vitro assays to test these hypotheses. Detailed analyses of the SH3BP2- and MyD88-mediated signaling pathway, the production of TNF-1 and their roles in inflammation and osteoclast activation will greatly contribute to better understanding of inflammatory bone disease in cherubism. Identifying the molecular components of these pathways and how they function will also aid in developing new targets for therapeutic intervention for other inflammatory diseases, such as rheumatoid arthritis and periodontal disease.

描述（由申请人提供）：“小天使症”是一种人类常染色体显性遗传病，其特征是过度骨吸收和下颌炎症纤维组织的积累。我们确定了导致这种人类疾病的基因，一种称为“SH3结构域结合蛋白2 （SH3BP2）”的信号接头蛋白，并确定了导致这种疾病的突变。为了进一步研究小天使病的发病机制，我们建立了一个携带该突变（小鼠P416R）的敲入小鼠模型。与人类疾病类似，小天使病小鼠表现出全身巨噬细胞驱动的炎症，肿瘤坏死因子- α (TNF-1)产生增加，破骨细胞分化增强，导致严重的全身炎症性骨质流失。因此，这些小鼠是有用的，不仅作为小天使病的模型，而且可能作为其他炎症性骨病的模型。所提出的研究的总体假设是，在小血管病相关炎性骨病中，TNF-1的错误表达和失调是通过髓系细胞中的SH3BP2信号介导的。我们提出SH3BP2突变导致巨噬细胞和破骨细胞前体对巨噬细胞集落刺激因子（M-CSF）和核因子- kb受体激活因子（NF-KB）配体（RANKL）的异常信号传导。我们还提出，过度活跃的巨噬细胞是导致TNF-1升高的原因，而TNF-1可以通过突变体SH3BP2反馈进一步激活已经过度活跃的破骨细胞。我们的初步数据表明，ERK和MyD88参与过度活跃的巨噬细胞产生TNF- 1，而Syk和NFATc1参与破骨细胞过度激活。为了验证这些假设，我们提出了以下具体目标：1)确定SH3BP2调控巨噬细胞TNF-1产生的机制；2)确定SH3BP2在nfatc1介导的破骨细胞分化中的作用；3)确定myd88介导的信号通路在小天使炎症发病机制中的作用。小天使小鼠模型将与其他小鼠模型（如SHP-1和MyD88缺失小鼠）杂交，并结合相关的体外分析来验证这些假设。详细分析SH3BP2-和myd88介导的信号通路、TNF-1的产生及其在炎症和破骨细胞活化中的作用，将极大地有助于更好地了解小天使炎症性骨病。确定这些途径的分子成分及其功能也将有助于开发其他炎症性疾病（如类风湿关节炎和牙周病）治疗干预的新靶点。

项目成果

Cherubism Mice Also Deficient in c-Fos Exhibit Inflammatory Bone Destruction Executed by Macrophages That Express MMP14 Despite the Absence of TRAP+ Osteoclasts.

Cherubism小鼠也缺乏C-FOS表现出巨噬细胞执行的炎症骨破坏，尽管没有陷阱+破骨细胞，但表达MMP14。

• DOI: 10.1002/jbmr.3295
• 发表时间: 2018-01
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Kittaka M;Mayahara K;Mukai T;Yoshimoto T;Yoshitaka T;Gorski JP;Ueki Y
• 通讯作者: Ueki Y

Loss of SH3 domain-binding protein 2 function suppresses bone destruction in tumor necrosis factor-driven and collagen-induced arthritis in mice.

• DOI: 10.1002/art.38975
• 发表时间: 2015-03
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: Mukai, Tomoyuki;Gallant, Richard;Ishida, Shu;Kittaka, Mizuho;Yoshitaka, Teruhito;Fox, David A.;Morita, Yoshitaka;Nishida, Keiichiro;Rottapel, Robert;Ueki, Yasuyoshi
• 通讯作者: Ueki, Yasuyoshi

SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model.

• DOI: 10.1371/journal.pone.0105518
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mukai T;Gallant R;Ishida S;Yoshitaka T;Kittaka M;Nishida K;Fox DA;Morita Y;Ueki Y
• 通讯作者: Ueki Y

Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-α-induced inflammation and bone loss.

• DOI: 10.1002/jbmr.2125
• 发表时间: 2014
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Yoshitaka, Teruhito;Ishida, Shu;Mukai, Tomoyuki;Kittaka, Mizuho;Reichenberger, Ernst J.;Ueki, Yasuyoshi
• 通讯作者: Ueki, Yasuyoshi

SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss.

SH3BP2天使突变通过NFATC1和TNF-α介导的炎症性骨质流失增强了TNF-α诱导的破骨细胞生成。

• DOI: 10.1002/jbmr.2295
• 发表时间: 2014-12
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Mukai, Tomoyuki;Ishida, Shu;Ishikawa, Remi;Yoshitaka, Teruhito;Kittaka, Mizuho;Gallant, Richard;Lin, Yi-Ling;Rottapel, Robert;Brotto, Marco;Reichenberger, Ernst J.;Ueki, Yasuyoshi
• 通讯作者: Ueki, Yasuyoshi