title: Anti-RANKL treatment inhibits erosive joint destruction and lowers inflammation but has no effect on bone formation in the delayed-type hypersensitivity arthritis (DTHA) model.
abstract: BACKGROUND
  The aims of the present study were to determine the relationship between bone destruction and bone formation in the delayed-type hypersensitivity arthritis (DTHA) model and to evaluate the effect of receptor activator of nuclear factor κB ligand (RANKL) blockade on severity of arthritis, bone destruction, and bone formation.
  
  
  METHODS
  DTHA was induced in C57BL/6 mice. Inflammation, erosive joint damage, and new bone formation were semiquantitatively scored by histology. Osteoclast activity was assessed in vivo, and messenger RNA (mRNA) expression of mediators of bone destruction and bone formation were analyzed by mRNA deep sequencing. Serum concentrations of tartrate-resistant acid phosphatase 5b, carboxy-terminal telopeptide I (CTX-I), matrix metalloproteinase 3 (MMP3), and serum amyloid P component (SAP) were determined by enzyme-linked immunosorbent assay. Anti-RANKL monoclonal antibody treatment was initiated at the time of immunization.
  
  
  RESULTS
  Bone destruction (MMP3 serum levels, cathepsin B activity, and RANKL mRNA) peaked at day 3 after arthritis induction, followed by a peak in cartilage destruction and bone erosion on day 5 after arthritis induction. Periarticular bone formation was observed from day 10. Induction of new bone formation indicated by enhanced Runx2, collagen X, osteocalcin, MMP2, MMP9, and MMP13 mRNA expression was observed only between days 8 and 11. Anti-RANKL treatment resulted in a modest reduction in paw and ankle swelling and a reduction of serum levels of SAP, MMP3, and CTX-I. Destruction of the subchondral bone was significantly reduced, while no effect on bone formation was seen.
  
  
  CONCLUSIONS
  Anti-RANKL treatment prevents joint destruction but does not prevent new bone formation in the DTHA model. Thus, although occurring sequentially during the course of DTHA, bone destruction and bone formation are apparently not linked in this model.
authors.affiliation: Global Research, Novo Nordisk A/S, 2760, Måløv, Denmark. saii@novonordisk.com.|Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, C, Denmark. saii@novonordisk.com.
authors.forename: Sara Marie
authors.initials: SM
authors.lastname: Atkinson
authors.affiliation: Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. janine.bleil@gmx.de.
authors.forename: Janine
authors.initials: J
authors.lastname: Bleil
authors.affiliation: German Rheumatism Research Center, Berlin, Germany. rene.maier@drfz.de.
authors.forename: René
authors.initials: R
authors.lastname: Maier
authors.affiliation: Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. anja.kuehl@charite.de.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Bioneer, Hørsholm, Denmark. mth@bioneer.dk.
authors.forename: Mette
authors.initials: M
authors.lastname: Thorn
authors.affiliation: Benaroya Research Institute, Seattle, WA, USA. kserikawa@benaroyaresearch.org.
authors.forename: Kyle
authors.initials: K
authors.lastname: Serikawa
authors.affiliation: Immunexpress, Seattle, WA, USA. bandrewfox@gmail.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Fox
authors.affiliation: Global Research, Novo Nordisk, Seattle, WA, USA. kimkruse911@gmail.com.
authors.forename: Kim
authors.initials: K
authors.lastname: Kruse
authors.affiliation: Global Research, Novo Nordisk A/S, 2760, Måløv, Denmark. csha@novonordisk.com.
authors.forename: Claus
authors.initials: C
authors.lastname: Haase
authors.affiliation: Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, C, Denmark. sosk@sund.ku.dk.
authors.forename: Søren
authors.initials: S
authors.lastname: Skov
authors.affiliation: Department of Pharmacology, Zealand Pharma, Glostrup, Denmark. ana@zealandpharma.com.
authors.forename: Anneline
authors.initials: A
authors.lastname: Nansen
authors.affiliation: Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. uta.syrbe@charite.de.|German Rheumatism Research Center, Berlin, Germany. uta.syrbe@charite.de.
authors.forename: Uta
authors.initials: U
authors.lastname: Syrbe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007596:Joints / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
chemical_list: D000911:Antibodies, Monoclonal; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse