Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis. Issue 9 (9th October 2015)

• Record Type: Journal Article
• Authors: Mediero, Aránzazu; Ramkhelawon, Bhama; Wilder, Tuere; Purdue, P Edward; Goldring, Steven R; Dewan, M Zahidunnabi; Loomis, Cynthia; Moore, Kathryn J; Cronstein, Bruce N
• Is Part Of: Annals of the rheumatic diseases. Volume 75:Issue 9(2016)
• Page Start: 1706
• Page End: 1713
• Publication Date: 2015-10-09
• Subjects: Inflammation -- Treatment -- Bone Mineral Density; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2015-207593
• Languages: English
• ISSNs: 0003-4967

Abstract

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.