title: Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis.
abstract: Netrin-1 is a chemorepulsant and matrix protein expressed during and required for osteoclast differentiation, which also plays a role in inflammation by preventing macrophage egress. Because wear particle-induced osteolysis requires osteoclast-mediated destruction of bone, we hypothesised that blockade of Netrin-1 or Unc5b, a receptor for Netrin-1, may diminish this pathological condition.
  
  
  
  C57BL/6 mice, 6-8 weeks old, had 3 mg of ultrahigh-molecular-weight polyethylene particles implanted over the calvaria and then received 10 µg of monoclonal antibodies for Netrin-1 or its receptors, Unc5b and deleted in colon cancer (DCC), injected intraperitoneally on a weekly basis. After 2 weeks, micro-computed tomography and histology analysis were performed. Netrin-1 expression was analysed in human tissue obtained following primary prosthesis implantation or after prosthesis revision for peri-implant osteolysis and aseptic implant loosening.
  
  
  
  Weekly injection of anti-Netrin-1 or anti-Unc5b-antibodies significantly reduced particle-induced bone pitting in calvaria exposed to wear particles (46±4% and 49±3% of control bone pitting, respectively, p<0.001) but anti-DCC antibody did not affect inflammatory osteolysis (80±7% of control bone pitting, p=ns). Anti-Netrin-1 or anti-Unc5b, but not anti-DCC, antibody treatment markedly reduced the inflammatory infiltrate and the number of tartrate resistance acid phosphatase (TRAP)-positive osteoclasts (7±1, 4±1 and 14±1 cells/high power field (hpf), respectively, vs 12±1 cells/hpf for control, p<0.001), with no significant changes in alkaline phosphatase-positive osteoblasts on bone-forming surfaces in any antibody-treated group. Netrin-1 immunostaining colocalised with CD68 staining for macrophages. The peri-implant tissues of patients undergoing prosthesis revision surgery showed an increase in Netrin-1 expression, whereas there was little Netrin-1 expression in soft tissues removed at the time of primary joint replacement.
  
  
  
  These results demonstrate a unique role for Netrin-1 in osteoclast biology and inflammation and may be a novel target for prevention/treatment of inflammatory osteolysis.
authors.affiliation: Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Mediero
authors.affiliation: Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York, New York, USA.
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.affiliation: Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA.
authors.forename: Tuere
authors.initials: T
authors.lastname: Wilder
authors.affiliation: Hospital for Special Surgery, New York, New York, USA.
authors.forename: P Edward
authors.initials: PE
authors.lastname: Purdue
authors.affiliation: Hospital for Special Surgery, New York, New York, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldring
authors.affiliation: Office of Collaborative Sciences, NYU School of Medicine, New York, New York, USA.
authors.forename: M Zahidunnabi
authors.initials: MZ
authors.lastname: Dewan
authors.affiliation: Office of Collaborative Sciences, NYU School of Medicine, New York, New York, USA Department of Pathology, NYU School of Medicine, New York, New York, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Loomis
authors.affiliation: Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York, New York, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.affiliation: Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA.
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D010010:Osteoclasts / Q000502:physiology*; D010014:Osteolysis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D011095:Polyethylenes; D011956:Receptors, Cell Surface / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D012886:Skull / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011095:Polyethylenes; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C111601:ultra-high molecular weight polyethylene; D000075388:Netrin-1
keywords: Bone Mineral Density; Inflammation; Treatment