title: Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors.
abstract: BACKGROUND
  The interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.
  
  
  METHODS
  Human CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-kappaB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A-/- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice.
  
  
  RESULTS
  IL-17A upregulates the receptor activator for NF-kappaB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts.
  
  
  CONCLUSIONS
  Collectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases.
authors.affiliation: Discovery Research, Schering-Plough Biopharma (formerly DNAX Research, Inc,), 901 South California Avenue, Palo Alto, CA 94304, USA. iannis.adamopoulos@spcorp.com
authors.forename: Iannis E
authors.initials: IE
authors.lastname: Adamopoulos
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chao
authors.forename: Richard
authors.initials: R
authors.lastname: Geissler
authors.forename: Drake
authors.initials: D
authors.lastname: Laface
authors.forename: Wendy
authors.initials: W
authors.lastname: Blumenschein
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Terrill
authors.initials: T
authors.lastname: McClanahan
authors.forename: Edward P
authors.initials: EP
authors.lastname: Bowman
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002469:Cell Separation; D002478:Cells, Cultured; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D053245:RANK Ligand / Q000096:biosynthesis*; D013234:Stem Cells / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D015854:Up-Regulation
chemical_list: D020381:Interleukin-17; D053245:RANK Ligand; C505688:TNFSF11 protein, human