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

A growth factor protects against arthritis in mice by blocking tumor necrosis factor–dependent signaling. 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.

[1]  M. Feldmann,et al.  TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases , 2003, Nature Medicine.

[2]  W. Min,et al.  Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis. , 2006, The American journal of pathology.

[3]  H. Erdjument-Bromage,et al.  Conversion of Proepithelin to Epithelins Roles of SLPI and Elastase in Host Defense and Wound Repair , 2002, Cell.

[4]  C. H. Ong,et al.  Progranulin is a mediator of the wound response , 2003, Nature Medicine.

[5]  G. Kollias,et al.  Effect of phospholipase A2 inhibitory peptide on inflammatory arthritis in a TNF transgenic mouse model: a time-course ultrastructural study , 2004, Arthritis research & therapy.

[6]  D. Kioussis,et al.  Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. , 1991, The EMBO journal.

[7]  J. Flanagan,et al.  Proteoglycan-Specific Molecular Switch for RPTPσ Clustering and Neuronal Extension , 2011, Science.

[8]  Jian Q. Feng,et al.  Cartilage Oligomeric Matrix Protein Associates with Granulin-Epithelin Precursor (GEP) and Potentiates GEP-stimulated Chondrocyte Proliferation* , 2007, Journal of Biological Chemistry.

[9]  P. Taylor.  How do the efficacy and safety of abatacept and infliximab compare in the treatment of active RA? , 2009, Nature Clinical Practice Rheumatology.

[10]  Q. Tian,et al.  Granulin-epithelin precursor binds directly to ADAMTS-7 and ADAMTS-12 and inhibits their degradation of cartilage oligomeric matrix protein. , 2010, Arthritis and rheumatism.

[11]  Chuan-ju Liu,et al.  ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral Bone Growth by Associating with and Inactivating GEP Growth Factor , 2009, Molecular and Cellular Biology.

[12]  Jian Q. Feng,et al.  Granulin epithelin precursor: a bone morphogenic protein 2‐inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  R. Hrabal,et al.  The hairpin stack fold, a novel protein architecture for a new family of protein growth factors , 1996, Nature Structural Biology.

[14]  Yi Luan,et al.  ADAMTS-12 Associates with and Degrades Cartilage Oligomeric Matrix Protein* , 2006, Journal of Biological Chemistry.

[15]  B. Aggarwal.  Signalling pathways of the TNF superfamily: a double-edged sword , 2003, Nature Reviews Immunology.

[16]  P. Lipsky,et al.  TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. , 2006, Blood.

[17]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[18]  F. Ni,et al.  Structure dissection of human progranulin identifies well‐folded granulin/epithelin modules with unique functional activities , 2008, Protein science : a publication of the Protein Society.

[19]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[20]  P. Carmeliet,et al.  Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival , 2008, The Journal of cell biology.

[21]  C. Iadecola,et al.  Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice , 2010, The Journal of experimental medicine.

[22]  A. Olsen,et al.  Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene , 1995, Nature Genetics.

[23]  A. Bateman,et al.  The granulin gene family: from cancer to dementia , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[24]  W. Kong,et al.  ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  S. Abramson,et al.  Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin. , 2008, Osteoarthritis and cartilage.

[26]  J. Ashby.  References and Notes , 1999 .

[27]  C. Prange,et al.  Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia , 1995, Nature Genetics.

[28]  M. J. Fresnadillo Martínez,et al.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions , 2010, Nature Genetics.

[29]  S. Yamashita,et al.  HDL/apolipoprotein A-I binds to macrophage-derived progranulin and suppresses its conversion into proinflammatory granulins. , 2010, Journal of atherosclerosis and thrombosis.

[30]  Chuan-ju Liu.  The role of ADAMTS-7 and ADAMTS-12 in the pathogenesis of arthritis , 2009, Nature Clinical Practice Rheumatology.

[31]  A. Bateman,et al.  Cellular Localization of Gene Expression for Progranulin , 2000, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[32]  Allan R. Brasier,et al.  Identification of Direct Genomic Targets Downstream of the Nuclear Factor-κB Transcription Factor Mediating Tumor Necrosis Factor Signaling* , 2005, Journal of Biological Chemistry.

[33]  J. Ring,et al.  Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. , 2008, The Journal of clinical investigation.

[34]  Zhiheng He,et al.  Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis , 2003, Journal of Molecular Medicine.

[35]  Sudha Kumari,et al.  Protein Kinase C-θ Mediates Negative Feedback on Regulatory T Cell Function , 2010, Science.