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

Session Information

Date: Monday, November 14, 2016

Session 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 March 1, 2021.

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