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      NF-kappaB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction

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      Author(s): 1 ,
      Publication date (Electronic):
      Journal: Arthritis Research
      Publisher: BioMed Central
      Keywords: apoptosis, hyperplasia, inflammation, inhibitors, nuclear factor NFκB, rheumatoid arthritis, therapy

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          Abstract

          The transcription factor NF-κB has been well recognized as a pivotal regulator of inflammation in rheumatoid arthritis (RA), but recent developments revealed a broad involvement of NF-κB in other aspects of RA pathology, including development of T helper 1 responses, activation, abnormal apoptosis and proliferation of RA fibroblast-like synovial cells, and differentiation and activation of bone resorbing activity of osteoclasts. In agreement with this, studies in animal models of RA have demonstrated the high therapeutic efficacy of specific inhibitors of NF-κB pathway, indicating the feasibility of anti-NF-κB therapy for human disease.

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          Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.

          Y Y Kong, U Feige, I Sarosi … (1999)
          Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T cells is induced by antigen receptor engagement, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.
          Article 0 comments Cited 316 times – based on 0 reviews     Review now
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            Control of apoptosis by Rel/NF-kappaB transcription factors.

            M Barkett, T D Gilmore (1999)
            Apoptosis is a physiological process critical for organ development, tissue homeostasis, and elimination of defective or potentially dangerous cells in complex organisms. Apoptosis can be initiated by a wide variety of stimuli, which activate a cell suicide program that is constitutively present in most vertebrate cells. In diverse cell types, Rel/NF-kappaB transcription factors have been shown to have a role in regulating the apoptotic program, either as essential for the induction of apoptosis or, perhaps more commonly, as blockers of apoptosis. Whether Rel/NF-kappaB promotes or inhibits apoptosis appears to depend on the specific cell type and the type of inducer. An understanding of the role of Rel/NF-kappaB transcription factors in controlling apoptosis may lead to the development of therapeutics for a wide variety of human diseases, including neurodegenerative and immune diseases, and cancer.
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              NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1.

              D. Guttridge, C Albanese, J Y Reuther … (1999)
              Accumulating evidence implicates the transcription factor NF-kappaB as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-kappaB regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-kappaB functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-kappaB activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-kappaB activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-kappaB inhibits myogenesis. NF-kappaB regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-kappaB to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-kappaB is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G(1)-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-kappaB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-kappaB and reveal a mechanism to explain how NF-kappaB is involved in the early phases of the cell cycle to regulate cell growth and differentiation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Arthritis Res
                Title: Arthritis Research
                Publisher: BioMed Central (London )
                ISSN (Print): 1465-9905
                ISSN (Electronic): 1465-9913
                Publication date (Print): 2001
                Publication date (Electronic): 26 March 2001
                Volume: 3
                Issue: 4
                Pages: 200-206
                Affiliations
                [1 ]Center for Inflammatory Disorders, Thurston Arthritis Research Center, and Department of Endodontics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
                Article
                Publisher ID: ar300
                DOI: 10.1186/ar300
                PMC ID: 128895
                PubMed ID: 11438035
                SO-VID: 2777b5a4-9af3-4de0-9d67-7ff111bf49d4
                Copyright © Copyright © 2001 BioMed Central Ltd
                History
                Date received : 2 January 2001
                Date revision requested : 26 February 2001
                Date revision received : 6 March 2001
                Date accepted : 8 March 2001
                Categories
                Subject: Commentary

                ScienceOpen disciplines: Orthopedics
                Keywords: nuclear factor nfκb,inflammation,hyperplasia,apoptosis,rheumatoid arthritis,therapy,inhibitors
                Data availability:
                ScienceOpen disciplines: Orthopedics
                Keywords: nuclear factor nfκb, inflammation, hyperplasia, apoptosis, rheumatoid arthritis, therapy, inhibitors

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