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Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis
  1. Aránzazu Mediero1,
  2. Bhama Ramkhelawon2,
  3. Tuere Wilder1,
  4. P Edward Purdue3,
  5. Steven R Goldring3,
  6. M Zahidunnabi Dewan4,
  7. Cynthia Loomis4,5,
  8. Kathryn J Moore2,
  9. Bruce N Cronstein1
  1. 1Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA
  2. 2Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York, New York, USA
  3. 3Hospital for Special Surgery, New York, New York, USA
  4. 4Office of Collaborative Sciences, NYU School of Medicine, New York, New York, USA
  5. 5Department of Pathology, NYU School of Medicine, New York, New York, USA
  1. Correspondence to Dr Bruce N Cronstein, Division of Translational Medicine, Department of Medicine, New York University School of Medicine, 550 First Avenue, MSB251, New York, NY 10016, USA; Bruce.Cronstein{at}nyumc.org

Abstract

Objective 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.

Methods 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.

Results 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.

Conclusions 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.

  • Inflammation
  • Treatment
  • Bone Mineral Density

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