NLRP3 inflammasome Regulation of Bone Resorption

描述（由申请人提供）：Nod富含亮氨酸的重复序列与Pyrin结构域3 （NLRP3）炎性体是一种细胞内蛋白复合物，负责白细胞介素(IL)-1¿和IL-18的成熟。NLRP3的功能获得性突变导致新生儿发病的多系统炎症（NOMID）。NOMID患者产生过量的IL-1 -¿，并表现出骨骼畸形和骨质减少，这表明组成型激活的NLRP3 （NOMID NLRP3）显著影响骨重塑。这些患者的关节病病变对IL-1靶向治疗难治性的发现表明，IL-1的产生可能不是NOMID NLRP3在骨骼中作用的唯一机制。事实上，这种炎性小体也参与了聚（adp -核糖）聚合酶1 （PARP1）的裂解，这是NF-？B共激活和破骨细胞（OC）发育。然而，骨量减少本身是否对IL-1抑制剂具有难治性尚不清楚。我们发现

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.