Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.

Original publication

DOI

10.1126/science.1199214

Type

Journal article

Journal

Science (New York, N.Y.)

Publication Date

04/2011

Volume

332

Pages

478 - 484

Addresses

Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.

Keywords

Cartilage, Articular, Animals, Mice, Inbred Strains, Mice, Transgenic, Mice, Knockout, Humans, Mice, Arthritis, Experimental, Intercellular Signaling Peptides and Proteins, Tumor Necrosis Factor-alpha, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Recombinant Proteins, Recombinant Fusion Proteins, Anti-Inflammatory Agents, Non-Steroidal, Ligands, Signal Transduction, Adolescent, Adult, Aged, Middle Aged, Female, Male, T-Lymphocytes, Regulatory, Protein Interaction Domains and Motifs, Young Adult