title: Defective nuclear factor-κB-inducing kinase in aly/aly mice prevents bone resorption induced by local injection of lipopolysaccharide.
abstract: OBJECTIVE
  Nuclear factor-κB (NF-κB) is activated at sites of inflammation in many diseases, including periodontitis. Nuclear factor-κB induces the transcription of proinflammatory cytokines, resulting in increased osteoclastogenesis and bone resorption. Recently, it has been shown that the NF-κB alternative pathway is important for maintainance of physiological bone homeostasis. Activation of this pathway is by processing of the inhibitor p100 into the active subunit p52 by nuclear factor-κB-inducing kinase (NIK). Defective NIK in aly/aly mice (NIK(aly)) causes mild osteopetrosis and blunted RANKL-stimulated osteoclastogenesis in vivo and in vitro, suggesting that NIK is necessary for basal and stimulated osteoclastogenesis. Nevertheless, the role of NIK in pathological bone resorption is not well investigated. The present study was undertaken to investigate the role of NIK in lipopolysaccharide (LPS)-induced inflammatory bone resorption using aly/aly mice.
  
  
  METHODS
  Mice were injected with LPS over the calvariae and killed 5 d later. Calvariae were subjected to radiological analysis. Histological sections were stained for tartrate-resistant acid phosphatase, and histomorphometric analysis was performed to quantify the number of osteoclasts and the area of bone resorption.
  
  
  RESULTS
  Lipopolysaccharide-induced inflammation was observed in wild-type and aly/+ mice but not in aly/aly mice. Lipopolysaccharide significantly reduced the calvarial bone mineral density in wild-type and aly/+ mice, whereas bone mineral density was comparable in LPS- and vehicle-injected aly/aly mice. In addition, aly/aly mice were resistant to LPS-induced bone resorption and osteoclastogenesis.
  
  
  CONCLUSIONS
  Taken together, these data show that NIK is important in the bone-destructive components of inflammation and represents a possible therapeutic target.
authors.affiliation: Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. niroshani.hpha@tmd.ac.jp
authors.forename: N S
authors.initials: NS
authors.lastname: Soysa
authors.forename: N
authors.initials: N
authors.lastname: Alles
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Aoki
authors.forename: K
authors.initials: K
authors.lastname: Ohya
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000209:etiology* / Q000473:pathology; D007091:Image Processing, Computer-Assisted / Q000379:methods; D021621:Imaging, Three-Dimensional / Q000379:methods; D007527:Isoenzymes / Q000032:analysis; D008070:Lipopolysaccharides / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000502:physiology*; D052003:NF-kappa B p52 Subunit / Q000502:physiology*; D010000:Osteitis / Q000209:etiology / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012886:Skull / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D014057:Tomography, X-Ray Computed / Q000379:methods; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000135:Acid Phosphatase; D015415:Biomarkers; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D000071681:Tartrate-Resistant Acid Phosphatase; D000097782:NF-kappaB-Inducing Kinase