A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, South Korea.
Journal of Experimental Medicine (Impact Factor: 12.52). 03/2012; 209(4):871-86. DOI: 10.1084/jem.20111783
Source: PubMed


An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress-associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1β, increased the expression of GRP78/BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down-regulation of Grp78 transcripts increased the apoptosis of RA synoviocytes while abolishing TNF- or TGF-β-induced synoviocyte proliferation and cyclin D1 up-regulation. Conversely, overexpression of the Grp78 gene prevented synoviocyte apoptosis. Moreover, Grp78 small interfering RNA inhibited VEGF(165)-induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with Grp78 haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA.

Download full-text


Available from: Sungyong You
  • Source
    • "ER stress-induced inflammation is also associated with other metabolic (Kawasaki et al., 2012; Papa, 2012; Tripathi and Pandey, 2012; McAlpine and Werstuck, 2013; Zhou and Tabas, 2013; Biden et al., 2014), inflammatory (Blohmke et al., 2012; Blumental-Perry, 2012; Yoo et al., 2012; Qiu et al., 2013; Savic et al., 2014), neurodegenerative diseases (Bellucci et al., 2011; Cunnea et al., 2011; McMahon et al., 2012; Vidal et al., 2012; Cornejo and Hetz, 2013; Mercado et al., 2013; Li et al., 2014), pathogen infections (Martinon et al., 2010; Merquiol et al., 2011; Tesh, 2012; Lee et al., 2013; Blazquez et al., 2014; Chan, 2014), and cancer (Shuda et al., 2003; Kubisch and Logsdon, 2008; Romero-Ramirez et al., 2009; Hardy et al., 2012; Tang et al., 2012; Chen et al., 2013; Mahoney et al., 2013; Kharabi Masouleh et al., 2014; Martin-Perez et al., 2014; Shimodaira et al., 2014; Zheng et al., 2014). While this review focuses on liver steatosis and inflammatory bowl diseases, Table 1 listed various diseases where pathogenesis has directly or indirectly been linked to ER stress. "
    [Show abstract] [Hide abstract]
    ABSTRACT: As an adaptive response to the overloading with misfolded proteins in the endoplasmic reticulum (ER), ER stress plays critical roles in maintaining protein homeostasis in the secretory pathway to avoid damage to the host. Such a conserved mechanism is accomplished through three well-orchestrated pathways known collectively as unfolded protein response (UPR). Persistent and pathological ER stress has been implicated in a variety of diseases in metabolic, inflammatory, and malignant conditions. Furthermore, ER stress is directly linked with inflammation through UPR pathways, which modulate transcriptional programs to induce the expression of inflammatory genes. Importantly, the inflammation induced by ER stress is directly responsible for the pathogenesis of metabolic and inflammatory diseases. In this review, we will discuss the potential signaling pathways connecting ER stress with inflammation. We will also depict the interplay between ER stress and inflammation in the pathogenesis of hepatic steatosis, inflammatory bowel diseases and colitis-associated colon cancer.
    Full-text · Article · Jul 2014 · Frontiers in Genetics
  • Source
    • "In addition, VEGF165-induced tube formation, migration, and chemotaxis of endothelial cells are also markedly reduced by knockdown of GRP78. These results, together with previous reports (38, 79, 80), indicate that GRP78 directly mediates VEGF165-induced migration, chemotaxis, and endothelial cell proliferation. Thus, anti-GRP78 inhibitors could be effective for suppressing the excessive angiogenesis frequently noted in RA joints. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by abnormal proliferation of synoviocytes, leukocyte infiltration, and angiogenesis. The endoplasmic reticulum (ER) is the site of biosynthesis for all secreted and membrane proteins. The accumulation of unfolded proteins in the ER leads to a condition known as ER stress. Failure of the ER's adaptive capacity results in abnormal activation of the unfolded protein response. Recently, we have demonstrated that ER stress-associated gene signatures are highly expressed in RA synovium and synovial cells. Mice with Grp78 haploinsufficiency exhibit the suppression of experimentally induced arthritis, suggesting that the ER chaperone GRP78 is crucial for RA pathogenesis. Moreover, increasing evidence has suggested that GRP78 participates in antibody generation, T cell proliferation, and pro-inflammatory cytokine production, and is therefore one of the potential therapeutic targets for RA. In this review, we discuss the putative, pathophysiological roles of ER stress and GRP78 in RA pathogenesis.
    Full-text · Article · Jan 2014 · Journal of Korean medical science
  • Source
    • "Some of the antigens described are joint-derived proteins, such as type II collagen and human cartilage-derived glycoprotein HCgp39 [7]. Other antigens are stress-associated proteins, including grp78/BiP, which is an intracellular chaperone involved in endoplasmic reticulum stress and angiogenesis in proliferative RA synovial tissue [8,9]. Endoplasmic reticulum stress may be provoked by many factors, including proinflammatory cytokines, cell death, misfolding of proteins in the endoplasmic reticulum, and reactive oxygen species [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disease resulting from an autoimmune response to self-antigens, leading to inflammation of synovial tissue of joints and subsequent cartilage and bone erosion. Current disease-modifying anti-rheumatic drugs and biologic inhibitors of TNF, IL-6, T cells and B cells block inflammation nonspecifically, which may lead to adverse effects, including infection. They do not generally induce long-term drug-free remission or restoration of immune tolerance to self-antigens, and lifelong treatment is usual. The development of antigen-specific strategies in RA has so far been limited by insufficient knowledge of autoantigens, of the autoimmune pathogenesis of RA and of the mechanisms of immune tolerance in man. Effective tolerance-inducing antigen-specific immunotherapeutic strategies hold promise of greater specificity, of lower toxicity and of a longer-term solution for controlling or even preventing RA. This paper reviews current understanding of autoantigens and their relationship to immunopathogenesis of RA, and emerging therapeutics that aim to leverage normal tolerance mechanisms for implementation of antigen-specific therapy in RA.
    Preview · Article · Feb 2013 · Arthritis research & therapy
Show more