PMID- 26452536 OWN - NLM STAT- MEDLINE DCOM- 20170601 LR - 20210420 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 75 IP - 9 DP - 2016 Sep TI - Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis. PG - 1706-13 LID - 10.1136/annrheumdis-2015-207593 [doi] AB - 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 microg 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. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ FAU - Mediero, Aranzazu AU - Mediero A AD - Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA. FAU - Ramkhelawon, Bhama AU - Ramkhelawon B AD - Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York, New York, USA. FAU - Wilder, Tuere AU - Wilder T AD - Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA. FAU - Purdue, P Edward AU - Purdue PE AD - Hospital for Special Surgery, New York, New York, USA. FAU - Goldring, Steven R AU - Goldring SR AD - Hospital for Special Surgery, New York, New York, USA. FAU - Dewan, M Zahidunnabi AU - Dewan MZ AD - Office of Collaborative Sciences, NYU School of Medicine, New York, New York, USA. FAU - Loomis, Cynthia AU - Loomis C AD - 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. FAU - Moore, Kathryn J AU - Moore KJ AD - Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York, New York, USA. FAU - Cronstein, Bruce N AU - Cronstein BN AD - Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA. LA - eng GR - P30 CA016087/CA/NCI NIH HHS/United States GR - R01 AR054897/AR/NIAMS NIH HHS/United States GR - K99 HL125667/HL/NHLBI NIH HHS/United States GR - R01 AR056672/AR/NIAMS NIH HHS/United States GR - UL1 TR000038/TR/NCATS NIH HHS/United States GR - R01 AR068593/AR/NIAMS NIH HHS/United States GR - UL1 TR001445/TR/NCATS NIH HHS/United States GR - RC1 HL100815/HL/NHLBI NIH HHS/United States GR - P30 AR046121/AR/NIAMS NIH HHS/United States GR - R56 AR056672/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151009 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - 0 (NTN1 protein, human) RN - 0 (Nerve Growth Factors) RN - 0 (Netrin Receptors) RN - 0 (Ntn1 protein, mouse) RN - 0 (Polyethylenes) RN - 0 (Receptors, Cell Surface) RN - 0 (Tumor Suppressor Proteins) RN - 0 (ultra-high molecular weight polyethylene) RN - 158651-98-0 (Netrin-1) SB - IM MH - Animals MH - Bone and Bones/metabolism/pathology MH - Inflammation MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Nerve Growth Factors/antagonists & inhibitors/*physiology MH - Netrin Receptors MH - Netrin-1 MH - Osteoclasts/*physiology MH - Osteolysis/chemically induced/*metabolism/pathology/prevention & control MH - Polyethylenes MH - Receptors, Cell Surface/administration & dosage/antagonists & inhibitors MH - Skull/metabolism/pathology MH - Tumor Suppressor Proteins/antagonists & inhibitors/*physiology PMC - PMC5349296 MID - NIHMS853586 OTO - NOTNLM OT - Bone Mineral Density OT - Inflammation OT - Treatment EDAT- 2015/10/11 06:00 MHDA- 2017/06/02 06:00 PMCR- 2017/09/01 CRDT- 2015/10/11 06:00 PHST- 2015/03/13 00:00 [received] PHST- 2015/09/20 00:00 [accepted] PHST- 2015/10/11 06:00 [entrez] PHST- 2015/10/11 06:00 [pubmed] PHST- 2017/06/02 06:00 [medline] PHST- 2017/09/01 00:00 [pmc-release] AID - annrheumdis-2015-207593 [pii] AID - 10.1136/annrheumdis-2015-207593 [doi] PST - ppublish SO - Ann Rheum Dis. 2016 Sep;75(9):1706-13. doi: 10.1136/annrheumdis-2015-207593. Epub 2015 Oct 9.