Journal Article

The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice

Yin, Fangfang, Syed, Nabeel Muzaffar, Dustin, Michael L., Feng, Jian Q., Craft, Joseph, Tian, Qing-Yun, Su, Jeffrey, Abramson, Steven B., Lin, Edward Alan, Kong, Li, Lai, Yongjie, Yin, Zhinan, Tang, Wei, Guo, Feng-Jin, Ding, Ai-Hao, Tao, Jian, Lu, Yi, Yu, Xiu-Ping, Liu, Chuan-ju, Zhang, Yan, Liu, Guang-Yi, Zanin-Zhorov, Alexandra

2011

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Adolescent / Adult / Aged / animal models / Animals / antagonists / Anti-Inflammatory Agents, Non-Steroidal - metabolism / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Anti-Inflammatory Agents, Non-Steroidal - therapeutic use / Antibodies / Antiinflammatories / Arthritis / Arthritis, Experimental - drug therapy / Arthritis, Experimental - immunology / Arthritis, Experimental - pathology / Arthritis, Experimental - physiopathology / Autoimmune diseases / Binding / Biological and medical sciences / Bones / carcinogenesis / Cartilage / Cartilage, Articular - metabolism / Cartilage, Articular - pathology / Collagens / Diseases of the osteoarticular system / embryogenesis / Embryonic growth stage / Female / Granulins / Growth factors / Humans / Immunization / Inflammation / Inflammatory joint diseases / Intercellular Signaling Peptides and Proteins - chemistry / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Intercellular Signaling Peptides and Proteins - therapeutic use / Ligands / Male / Medical sciences / Medical treatment / Mice / Mice, Inbred Strains / Mice, Knockout / Mice, Transgenic / Middle Aged / Pathogenesis / Pathology / Progranulins / Protein Interaction Domains and Motifs / Receptors / Receptors, Tumor Necrosis Factor, Type I - genetics / Receptors, Tumor Necrosis Factor, Type I - metabolism / Receptors, Tumor Necrosis Factor, Type II - genetics / Receptors, Tumor Necrosis Factor, Type II - metabolism / Recombinant Fusion Proteins - metabolism / Recombinant Fusion Proteins - pharmacology / Recombinant Fusion Proteins - therapeutic use / Recombinant Proteins - therapeutic use / Rheumatoid arthritis / Signal Transduction / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - physiology / tissue repair / tumor necrosis factor-alpha / Tumor Necrosis Factor-alpha - metabolism / Young Adult