title: NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms.
abstract: Activating-mutations in NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) cause neonatal-onset multisystem inflammatory disease. However, the ontogeny of skeletal anomalies in this disorder is poorly understood. Mice globally expressing the D301N mutation in Nlrp3 (D303N in human) model the human phenotype, including systemic inflammation and skeletal deformities. To gain insights into the skeletal manifestations, we generated mice in which the expression of D301N Nlrp3 (Nlrp3( D301N)) is restricted to myeloid cells. These mice exhibit systemic inflammation and severe osteopenia (∼ 60% lower bone mass) similar to mice globally expressing the knock-in mutation, consistent with the paradigm of innate immune-driven cryopyrinopathies. Because systemic inflammation may indirectly affect bone homeostasis, we engineered mice in which Nlrp3( D301N) is expressed specifically in osteoclasts, the cells that resorb bone. These mice also develop ∼ 50% lower bone mass due to increased osteolysis, but there is no systemic inflammation and no change in osteoclast number. Mechanistically, aside from its role in IL-1β maturation, Nlrp3( D301N) expression enhances osteoclast bone resorbing ability through reorganization of actin cytoskeleton while promoting the degradation of poly(ADP-ribose) polymerase 1, an inhibitor of osteoclastogenesis. Thus, NLRP3 inflammasome activation is not restricted to the production of proinflammatory mediators but also leads to cytokine-autonomous responses.
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Qu
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Bonar
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Hickman-Brecks
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Samer
authors.initials: S
authors.lastname: Abu-Amer
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Peña
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Broderick
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Yang
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Grimston
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Kading
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
authors.affiliation: *Division of Bone and Mineral Diseases and Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; and Division of Allergy, Immunology, and Rheumatology, University of California, San Diego, La Jolla, California, USA gmbalavi@dom.wustl.edu.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D056587:Cryopyrin-Associated Periodic Syndromes / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059748:Proteolysis
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D050505:Mutant Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: IL-1β; NOMID; PARP1; cryopyrinopathies; osteoclasts