title: 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: Bone and Joint Research Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.|Division of Translational Medicine, Department of Medicine, New York University School of Medicine, New York, New York, USA; and.
authors: Aránzazu
authors: A
authors: Mediero
authors: Division of Translational Medicine, Department of Medicine, New York University School of Medicine, New York, New York, USA; and.
authors: Tuere
authors: T
authors: Wilder
authors: Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors: Bhama
authors: B
authors: Ramkhelawon
authors: Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors: Kathryn J
authors: KJ
authors: Moore
authors: Division of Translational Medicine, Department of Medicine, New York University School of Medicine, New York, New York, USA; and bruce.cronstein@nyumc.org.
authors: Bruce N
authors: BN
authors: Cronstein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1
keywords: K/BxN; inflammation; rheumatoid arthritis