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Abstract Number: 1437

Netrin-1 and Its Receptor Unc5b Are Novel Targets for the Treatment of Inflammatory Arthritis

Aranzazu Mediero1, Tuere Wilder2, Bhama Ramkhelawon3, Kathryn Moore3 and Bruce Cronstein4, 1Medicine, Divison of Translational Medicine, NYU School of Medicine, New York City, NY, 2Department of Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY, 3Leon H. Charney Division of Cardiology, Department of Medicine,, NYU School of Medicine, New York, NY, 4Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Animal models, Antibodies, arthritis and treatment, Disease Activity

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Session Information

Date: Monday, November 14, 2016

Title: Rheumatoid Arthritis – Animal Models - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:  Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation and destruction of joints. Netrin-1, a laminin-like matrix protein that acts as a chemorepulsant, plays a pathogenic role during inflammation by preventing macrophage egress from inflamed sites, and it is required for osteoclast differentiation. We asked whether blockade of Netrin-1 or its receptors (Unc5b, DCC) may be useful therapeutic targets in the treatment of inflammatory arthritis.

Methods:  8wk-old-C57Bl/6 mice were ip-injected with 0.2ml K/BxN serum twice. Murine monoclonal antibodies against Netrin-1, Unc5b or DCC (10µg/mice) were ip-injected weekly for 4wk (n=10). Clinical signs (paw swelling and thickness) were observed daily. Animals were sacrificed 2-4wk after serum transfer, and paws were prepared for microCT and histology

Results:  Serum transfer induced an increase in paw inflammation that was maximal 2wk after injection. Anti-Netrin-1 or anti-Unc5b, but not anti-DCC, antibodies significantly reduced paw inflammation (clinical score of 9.8±0.8, 10.4±0.9 and 13.5±0.5 respectively vs. 16±0 for control, p<0.001, n=10). Same results were observed for changes in paw thickness. microCT showed bony erosions in untreated or anti-DCC-treated-mice whereas there were no erosions in anti-Netrin-1/anti-Unc5b-treated-animals. TRAPstaining demonstrated a marked decrease in osteoclasts in anti-Netrin-1/anti-Unc5b-treated-animals but not in anti-DCC-treated-mice (4±1, 3±1 and 9±2cells/hpf respectively vs.12±1cells/hpf for control, p<0.001 and p=ns, n=5). Immunofluorescence staining revealed a decrease Cathepsin K and CD68-positive cells in anti-Netrin-1/anti-Unc5b, but not anti-DCC-treated-animals.

Conclusion:  Blockade of Netrin-1/Unc5b by treatment with murine monoclonal antibodies prevents bone destruction and K/BxN serum transfer-induced arthritis. Netrin-1 may be a novel therapeutic target for inflammatory bone destruction.


Disclosure: A. Mediero, CP15/0053, 2, 9,Patent for the use of adenosine A2AR agonists to prevent prosthesis loosening. Patent on the use of Antibodies against Netrin-1 for the treatment of bone diseases., 9; T. Wilder, None; B. Ramkhelawon, patent on the use of Antibodies against Netrin-1 for the treatment of bone diseases., 9; K. Moore, patent on the use of Antibodies against Netrin-1 for the treatment of bone diseases., 9; B. Cronstein, Canfite Pharma, 1,Celgene, AstraZeneca, Takeda, 2,Revive Therapeutics, 5,Always hopeful, 9.

To cite this abstract in AMA style:

Mediero A, Wilder T, Ramkhelawon B, Moore K, Cronstein B. Netrin-1 and Its Receptor Unc5b Are Novel Targets for the Treatment of Inflammatory Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/netrin-1-and-its-receptor-unc5b-are-novel-targets-for-the-treatment-of-inflammatory-arthritis-2/. Accessed .
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