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Ann Rheum Dis. 2016 Sep;75(9):1706-13. doi: 10.1136/annrheumdis-2015-207593. Epub 2015 Oct 9.

Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis.

Author information

1
Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, New York, USA.
2
Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York, New York, USA.
3
Hospital for Special Surgery, New York, New York, USA.
4
Office of Collaborative Sciences, NYU School of Medicine, New York, New York, USA.
5
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.

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.

KEYWORDS:

Bone Mineral Density; Inflammation; Treatment

PMID:
26452536
PMCID:
PMC5349296
DOI:
10.1136/annrheumdis-2015-207593
[Indexed for MEDLINE]
Free PMC Article

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