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.

Public Health Relevance

The goal of this project is to understand the role of NLRP3 in bone loss. If this protein plays a role in bone loss, the future research would be to find a way to block the function of this protein in people with bone diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AR064755-02
Application #
8713938
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130