title: Interleukin-32 promotes osteoclast differentiation but not osteoclast activation.
abstract: BACKGROUND
  Interleukin-32 (IL-32) is a newly described cytokine produced after stimulation by IL-2 or IL-18 and IFN-gamma. IL-32 has the typical properties of a pro-inflammatory mediator and although its role in rheumatoid arthritis has been recently reported its effect on the osteoclastogenesis process remains unclear.
  
  
  RESULTS
  In the present study, we have shown that IL-32 was a potent modulator of osteoclastogenesis in vitro, whereby it promoted the differentiation of osteoclast precursors into TRAcP+ VNR+ multinucleated cells expressing specific osteoclast markers (up-regulation of NFATc1, OSCAR, Cathepsin K), but it was incapable of inducing the maturation of these multinucleated cells into bone-resorbing cells. The lack of bone resorption in IL-32-treated cultures could in part be explain by the lack of F-actin ring formation by the multinucleated cells generated. Moreover, when IL-32 was added to PBMC cultures maintained with soluble RANKL, although the number of newly generated osteoclast was increased, a significant decrease of the percentage of lacunar resorption was evident suggesting a possible inhibitory effect of this cytokine on osteoclast activation. To determine the mechanism by which IL-32 induces such response, we sought to determine the intracellular pathways activated and the release of soluble mediators in response to IL-32. Our results indicated that compared to RANKL, IL-32 induced a massive activation of ERK1/2 and Akt. Moreover, IL-32 was also capable of stimulating the release of IL-4 and IFN-gamma, two known inhibitors of osteoclast formation and activation.
  
  
  CONCLUSIONS
  This is the first in vitro report on the complex role of IL-32 on osteoclast precursors. Further clarification on the exact role of IL-32 in vivo is required prior to the development of any potential therapeutic approach.
authors.affiliation: Nuffield Department of Orthopaedic Surgery, University of Oxford, Oxford, UK. guillaume.mabilleau@ndos.ox.ac.uk
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mabilleau
authors.forename: Afsie
authors.initials: A
authors.lastname: Sabokbar
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000166:cytology* / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002417:Cattle; D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C496971:IL32 protein, human; D007378:Interleukins; D053244:Osteoprotegerin; D053245:RANK Ligand; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1