title: Inhibition of T cell-dependent and RANKL-dependent osteoclastogenic processes associated with high levels of bone mass in interleukin-15 receptor-deficient mice.
abstract: OBJECTIVE
  T cell production of RANKL, interferon-γ (IFNγ), and other cytokines in inflammatory processes such as rheumatoid arthritis or secondary to conditions such as estrogen deficiency stimulates osteoclast activity, which leads to bone resorption and bone loss. The purpose of this study was to characterize the effects of interleukin-15 (IL-15), a master T cell growth factor whose role in bone remodeling remains unknown.
  
  
  METHODS
  We used mice lacking the IL-15 receptor (IL-15Rα(-/-) ) to investigate the effects of IL-15 on osteoclast development, T cell and dendritic cell activation in vitro and in vivo, bone mass, and microarchitecture in intact and ovariectomized (OVX) mice.
  
  
  RESULTS
  In wild-type (WT) animals, IL-15 and RANKL provided a costimulatory signal for osteoclast development. Spleens from IL-15Rα(-/-) mice contained few c-Kit+ osteoclast precursors, and the expression of NF-ATc1 and the osteoclastogenic response to RANKL were impaired. In addition, dendritic cell-dependent and T cell-dependent mechanisms of osteoclast activation, including RANKL and IFNγ production, were impaired in IL-15Rα(-/-) mice. In turn, IL-15Rα(-/-) T cells failed to stimulate WT osteoclasts, whereas WT T cells failed to stimulate IL-15Rα(-/-) osteoclasts. Compared with WT mice, both intact and OVX IL-15Rα(-/-) mice had significantly greater bone mineral density and microarchitecture, including a higher trabecular bone volume fraction and cortical thickness. The numbers of osteoclasts on the bone surface as well as markers of bone turnover were significantly decreased in IL-15Rα(-/-) mice.
  
  
  CONCLUSIONS
  In the absence of IL-15 signaling, several converging mechanisms of osteoclastogenesis are inhibited, both directly and indirectly, through T cells, which leads to a high bone mass phenotype. Targeting the IL-15 pathway may represent a novel therapeutic approach to treating primary and secondary osteoporosis.
authors.affiliation: World Health Organization Collaborating Center for Osteoporosis Prevention, Geneva University Medical School, and Geneva University Hospital, Geneva, Switzerland.
authors.forename: Souad
authors.initials: S
authors.lastname: Djaafar
authors.forename: Dominique D
authors.initials: DD
authors.lastname: Pierroz
authors.forename: Rachel
authors.initials: R
authors.lastname: Chicheportiche
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: Serge L
authors.initials: SL
authors.lastname: Ferrari
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ferrari-Lacraz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015519:Bone Density; D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D053647:Receptors, Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D053245:RANK Ligand; D053647:Receptors, Interleukin-15; C505689:Tnfsf11 protein, mouse