title: NLRP12 provides a critical checkpoint for osteoclast differentiation.
abstract: The alternative or noncanonical nuclear factor kappa B (NF-κB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-κB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-κB-induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro observations dovetail with our in vivo findings that NLRP12 deficiency leads to enhanced OC numbers accompanied by a significant decline in bone mass under physiological conditions. Consistent with the basal bone phenotype, we also observed an enhanced osteolytic response following RANKL injection over the calvaria of NLRP12-deficient chimeric mice compared with wild-type control mice. Thus, modulation of NLRP12 levels controls alternative NF-κB signaling in OC precursors, altering bone homeostasis and osteolytic responses.
authors.affiliation: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Krauss
authors.affiliation: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.affiliation: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Hickman-Brecks
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599; Inflammatory Diseases Institute, University of North Carolina School of Medicine, Chapel Hill, NC 27599;
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599; Inflammatory Diseases Institute, University of North Carolina School of Medicine, Chapel Hill, NC 27599; Departments of Genetics, Microbiology, and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599; novack@wustl.edu jenny_ting@med.unc.edu.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.affiliation: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110 novack@wustl.edu jenny_ting@med.unc.edu.
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D015151:Immunoblotting; D007249:Inflammation / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009711:Nucleotides / Q000737:chemistry; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D052002:NF-kappa B p50 Subunit; C553199:NLRP12 protein, mouse; D009711:Nucleotides; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C073701:Nfkb1 protein, mouse; D007930:Leucine
keywords: NLRP12; alternative NF-κB; bone; osteoclast