The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice.

Journal article

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.

Authors: Tang, W; Lu, Y; Tian, Q; Zhang, Y; Guo, F

• Journal: Science (New York, N.Y.)
• Volume: 332
• Issue: 6028
• Pages: 478-484
• Publication date: 2011-04-01
• DOI: 10.1126/science.1199214
• EISSN: 1095-9203
• ISSN: 0036-8075
• Language: English
• Keywords: Protein Interaction Domains and Motifs; Adolescent; Adult; Receptors, Tumor Necrosis Factor, Type I; T-Lymphocytes, Regulatory; Cartilage, Articular; Recombinant Fusion Proteins; Intercellular Signaling Peptides and Proteins; Aged; Animals; Signal Transduction; Young Adult; Mice, Inbred Strains; Anti-Inflammatory Agents, Non-Steroidal; Female; Middle Aged; Ligands; Mice, Transgenic; Arthritis, Experimental; Humans; Receptors, Tumor Necrosis Factor, Type II; Mice, Knockout; Recombinant Proteins; Mice; Tumor Necrosis Factor-alpha; Male