Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis.

Abstract

Rheumatoid arthritis is an autoimmune disease that is characterized by chronic inflammation and destruction of joints. Netrin-1, a chemorepulsant, laminin-like matrix protein, promotes inflammation by preventing macrophage egress from inflamed sites and is required for osteoclast differentiation. We asked whether blockade of Netrin-1 or its receptors [Unc5b and DCC (deleted in colorectal carcinoma)] may be useful therapeutic targets for treatment of inflammatory arthritis. Arthritis was induced in 8-wk-old C57Bl/6 mice by intraperitoneal injection of K/BxN serum. Murine monoclonal antibodies against Netrin-1, Unc5b, or DCC (10 µg/mouse) were injected weekly for 4 wk (n = 10). Paw swelling and thickness were assessed and following euthanasia 2-4 wk after serum transfer, paws were prepared for micro-computed tomography and histology. Paw inflammation was maximal 2 wk after injection. Anti-Netrin-1 or anti-Unc5b, but not anti-DCC, antibodies significantly reduced paw inflammation (clinical score: 9.8 ± 0.8, 10.4 ± 0.9, and 13.5 ± 0.5, respectively vs 16 ± 0 for control; P < 0.001). Micro-computed tomography showed bony erosions in untreated or anti-DCC-treated mice, whereas there were no erosions in anti-Netrin-1/anti-Unc5b-treated-animals. Tartrate-resistant acid phosphatase staining demonstrated a marked decrease in osteoclasts in anti-Netrin-1/anti-Unc5b-treated animals. Immunofluorescence staining revealed a decrease in cathepsin K+ and CD68+ cells in anti-Netrin-1/anti-Unc5b-treated animals. Blockade of Netrin-1/Unc5b by monoclonal antibodies prevents bone destruction and reduces the severity of K/BxN serum transfer-induced arthritis. Netrin-1 may be a novel therapeutic target for treatment of inflammatory bone destruction.-Mediero, A., Wilder, T., Ramkhelawon, B., Moore, K. J., Cronstein, B. N. Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis.

• Authors: Aránzazu Mediero, Tuere Wilder, Bhama Ramkhelawon, Kathryn J Moore, Bruce N Cronstein
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 30 Issue 11 Pg. 3835-3844 (11 2016) ISSN: 1530-6860 [Electronic] United States
• PMID: 27502509 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Antibodies, Monoclonal
• Nerve Growth Factors
• Netrin Receptors
• Ntn1 protein, mouse
• Receptors, Cell Surface
• Tumor Suppressor Proteins
• Netrin-1

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Arthritis, Rheumatoid (drug therapy, immunology)
• Disease Models, Animal
• Inflammation (drug therapy, immunology)
• Macrophages (drug effects, metabolism)
• Mice, Transgenic
• Nerve Growth Factors (genetics, metabolism)
• Netrin Receptors
• Netrin-1
• Osteoclasts (drug effects, metabolism)
• Receptors, Cell Surface (metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)