NLRP3 inflammasome Regulation of Bone Resorption

NLRP3 炎性体对骨吸收的调节

• 批准号: 8713938
• 负责人: Gabriel Mbalaviele
• 金额: $ 32.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713938
• 关键词: Ablation; Bone Diseases; Bone Matrix; Bone Resorption; Bone remodeling; Cells; Clinical; Data; Deformity; Development; Disease; Disease model; Estrogens; Exhibits; Feedback; Genetic Models; Goals; Growth; Human; Hyperparathyroidism; Inflammation; Inflammatory; Interleukin-1; Interleukin-18; Lesion; Leucine-Rich Repeat; Light; Mediator of activation protein; Minerals; Modeling; Mus; Myeloid Cells; NF-kappa B; Neonatal; Osteoclasts; Osteopenia; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiologic calcification; Play; Poly(ADP-ribose) Polymerases; Positioning Attribute; Production; Proteins; Refractory; Regulation; Reporting; Role; Signal Transduction; Skeleton; Syndrome; System; Testing; Therapeutic Intervention; arthropathies; bone; bone loss; bone mass; bone turnover; clinically relevant; gain of function mutation; inhibitor/antagonist; malformation; marenostrin; mouse model; neonatal human; novel; prevent; protein complex; protein function; public health relevance; skeletal; therapeutic target

DESCRIPTION (provided by applicant): The Nod Leucine rich Repeat with a Pyrin domain 3 (NLRP3) inflammasome is an intracellular protein complex responsible for the maturation of interleukin (IL)-1¿ and IL-18. Gain-of-function mutations of NLRP3 cause neonatal-onset multisystem inflammatory disease (NOMID). NOMID patients produce excessive amounts of IL-1¿, and exhibit skeletal deformities and osteopenia, suggesting that constitutively activated NLRP3 (NOMID NLRP3) significantly impacts bone remodeling. The finding that arthropathic lesions in these patients are refractory to IL-1 targeted therapy suggests that IL-1 production may not be the only mechanism of NOMID NLRP3 action in the skeleton. Indeed, this inflammasome is also involved in the cleavage of poly(ADP-ribose) polymerase 1 (PARP1), a novel mechanism of NF-?B co- activation, and osteoclast (OC) development. However, whether osteopenia per se in NOMID patients is refractory to IL-1 inhibitors is still unclear. We find that mice globally expressing NOMID NLRP3 mimic the human NOMID syndrome as they over-produce IL-1¿ and diminished bone mass. Further preliminary data suggest a broader role of this inflammasome in bone remodeling. First, mice expressing NOMID NLRP3, specifically in myeloid cells or in OC also have low bone mass, suggesting an OC lineage action of this inflammasome. Second, NLRP3 inflammasome promotes PARP1 cleavage and OC formation, while PARP1 knockdown inhibits OC formation. This suggests that inflammasome promotion of PARP1 cleavage may be an alternative mechanism of bone resorption over IL-1¿ production. Finally, bone matrix degradation products activate NLRP3, and stimulate OC formation, implying that this inflammasome may be active in all states of high bone turnover. Thus, our preliminary data suggest that NLRP3 inflammasome activation is not restricted to inflammatory conditions, and may represent a fundamental positive feedback loop that amplifies bone resorption. The central hypothesis of this proposal is that the NLRP3 inflammasome is a multifunctional regulator of bone resorption in inflammatory and non-inflammatory conditions characterized by high bone turnover. To test this hypothesis, we will use mouse genetic models and human cell systems to: 1) Define the role of PARP1 and IL-1¿ in bone resorption caused by NOMID NLRP3 inflammasome; 2) Investigate the role and the mechanisms of activation of this inflammasome in non-inflammatory conditions of high bone turnover. Upon completion, this project will establish that this inflammasome plays a significant role in inflammatory and non-inflammatory bone loss, thus positioning it as a potential therapeutic target for diseases of bone loss.

描述（由应用提供）：与吡啶结构域3（NLRP3）炎性体的点头富含Leucine Reply是一种细胞内蛋白质复合物，负责白介素（IL）-1和IL-18的成熟。 NLRP3的功能性突变导致新生儿发作多系统炎症性疾病（NOMID）。候选患者产生过量的IL-1，并表现出骨骼畸形和骨质减少症，这表明组成型激活的NLRP3（Nomid NLRP3）显着影响骨重塑。这些患者的关节炎病变对IL-1靶向疗法难治性的发现表明，IL-1产生可能不是骨骼中NOMID NLRP3作用的唯一机制。实际上，这种炎症体也参与了聚（ADP-核糖）聚合酶1（PARP1）的裂解，NF- b co copotigation的新机理和骨细胞（OC）发育。然而，尚不清楚，在名称患者中，骨质减少症本身是否对IL-1抑制剂难治性尚不清楚。我们发现 全球表达NOMID NLRP3的小鼠模仿了人类综合征，因为它们过量生产IL-1并减少了骨骼质量。进一步的初步数据表明，该炎症体在骨骼重塑中的广泛作用。首先，表达NOMID NLRP3的小鼠，特别是在髓样细胞或OC中的小鼠也有低骨量，表明该炎症体的OC谱系作用。其次，NLRP3炎性体促进了PARP1裂解和OC的形成，而PARP1敲低抑制了OC的形成。这表明炎症体促进PARP1裂解可能是IL-1生产的骨修复的另一种机制。最后，骨基质降解产物激活NLRP3并刺激OC的形成，这意味着该炎症体在所有高骨更新的状态下都可能活跃。这就是我们的初步数据表明，NLRP3炎性体激活不仅限于炎症条件，并且可能代表放大骨骼分辨率的基本正反馈回路。该提议的中心假设是NLRP3炎症体是骨骼分辨率的多功能调节剂，在炎症和非炎症状态中，其特征是高骨转换。为了检验这一假设，我们将使用小鼠遗传模型和人类细胞系统来：1）定义PARP1和IL-1缺的作用在NOMID NLRP3炎性体引起的骨骼分辨率中； 2）研究该炎症体在高骨转换的非炎症条件下激活的作用和机制。完成后，该项目将确定该炎症体在炎症和非炎性骨质流失中起着重要作用，从而将其定位为骨质流失疾病的潜在治疗靶标。