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


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.

SUBMITTER: Mediero A 

PROVIDER: S-EPMC5349296 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Mediero Aránzazu A   Ramkhelawon Bhama B   Wilder Tuere T   Purdue P Edward PE   Goldring Steven R SR   Dewan M Zahidunnabi MZ   Loomis Cynthia C   Moore Kathryn J KJ   Cronstein Bruce N BN  

Annals of the rheumatic diseases 20151009 9


<h4>Objective</h4>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.<h4>Methods</h4>C57BL/6 mice, 6-8 weeks old, had 3 mg of ultrahigh-molecular-weight polyet  ...[more]

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