title: NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis.
abstract: BACKGROUND
  Maintenance of healthy bone requires the balanced activities of osteoclasts (OCs), which resorb bone, and osteoblasts, which build bone. Disproportionate action of OCs is responsible for the bone loss associated with postmenopausal osteoporosis and rheumatoid arthritis. NF-κB inducing kinase (NIK) controls activation of the alternative NF-κB pathway, a critical pathway for OC differentiation. Under basal conditions, TRAF3-mediated NIK degradation prevents downstream signaling, and disruption of the NIK:TRAF3 interaction stabilizes NIK leading to constitutive activation of the alternative NF-κB pathway.
  
  
  RESULTS
  Using transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), we now find that alternative NF-κB activation enhances not only OC differentiation but also OC function. Activating NT3 with either lysozyme M Cre or cathepsinK Cre causes high turnover osteoporosis with increased activity of OCs and osteoblasts. In vitro, NT3-expressing precursors form OCs more quickly and at lower doses of RANKL. When cultured on bone, they exhibit larger actin rings and increased resorptive activity. OC-specific NT3 transgenic mice also have an exaggerated osteolytic response to the serum transfer model of arthritis.
  
  
  CONCLUSIONS
  Constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli.
authors.affiliation: Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Chang
authors.initials: C
authors.lastname: Yang
authors.forename: Kathleen
authors.initials: K
authors.lastname: McCoy
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Davis
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Deborah Veis
authors.initials: DV
authors.lastname: Novack
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D015519:Bone Density; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism*; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D056657:Cathepsin K; D009113:Muramidase; D016328:NF-kappa B; D015675:Osteocalcin; D017346:Protein Serine-Threonine Kinases; D053245:RANK Ligand; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase; C505689:Tnfsf11 protein, mouse; C472450:lysozyme M, mouse