title: Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice.
abstract: The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue "spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling.
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Bonar
authors.forename: Susannah D
authors.initials: SD
authors.lastname: Brydges
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.forename: Carla
authors.initials: C
authors.lastname: Pena
authors.forename: Debbie
authors.initials: D
authors.lastname: Chen
authors.forename: Susan K
authors.initials: SK
authors.lastname: Grimston
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Hickman-Brecks
authors.forename: Soumya
authors.initials: S
authors.lastname: Ravindran
authors.forename: Audrey
authors.initials: A
authors.lastname: McAlinden
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
mesh_terms: D000818:Animals; D001846:Bone Development; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000150:complications / Q000473:pathology; D001842:Bone and Bones / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002458:Cell Fractionation; D019070:Cell Lineage; D049109:Cell Proliferation; D024043:Collagen Type II / Q000378:metabolism; D056587:Cryopyrin-Associated Periodic Syndromes / Q000150:complications / Q000473:pathology; D006132:Growth Plate / Q000002:abnormalities; D058847:Inflammasomes; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007596:Joints / Q000473:pathology; D007964:Leukocytosis / Q000150:complications / Q000473:pathology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D013194:Staining and Labeling; D016019:Survival Analysis
chemical_list: D002352:Carrier Proteins; D024043:Collagen Type II; D058847:Inflammasomes; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse