The role of apoptosis in rheumatoid arthritis
Introduction
The synovial tissue from patients with rheumatoid arthritis (RA) displays synovial lining hyperplasia as a result of accumulation of synovial fibroblasts and macrophages. These cells promote inflammation and joint destruction, which is mediated by the production of pro-inflammatory cytokines (e.g. tumour necrosis factor-α [TNFα] and interleukin [IL]-1), chemokines (e.g. IL-8 and monocyte chemoattractant protein-1), and proteinases (e.g. matrix metalloproteinases and cathepsins) [1]. Where the lining attaches to the bone–cartilage interface, activated osteoclasts also promote joint destruction by directly destroying the adjacent bone. In the sublining region, there is accumulation of chronic inflammatory cells, including lymphocytes and macrophages, and an abundant neovascular network. The mechanisms for the induction and persistence of RA are not known; however, insufficient apoptosis of synovial macrophages, fibroblasts and lymphocytes is one mechanism that might contribute to persistence of the disease [2••].
Section snippets
Mechanisms for the induction of apoptosis
Apoptosis or programmed cell death is an evolutionarily conserved, multi-step process by which a cell undergoes an orderly demise. In contrast to necrosis, the contents of the apoptotic cell are not released, and the cell is cleared by phagocytosis. Apoptosis can be initiated through death receptor- or mitochondria-dependent pathways (Figure 1). The death receptor-dependent pathway is initiated through ligation of specific death receptors by their ligands. The major death receptors include Fas
Fas death receptor pathway
Macrophages from the joints of patients with RA express both Fas and FasL [3]. Fas is also expressed by other cells within the joint, including synovial fibroblasts and lymphocytes. In certain areas, particularly the synovial lining, macrophages and fibroblasts are in close proximity, yet there is little evidence for ongoing apoptosis [2••]. Several studies have examined the mechanisms that could contribute to the resistance against Fas-mediated apoptosis in RA. Flip is more highly expressed in
Inhibition of NF-κB and death-receptor-mediated apoptosis
NF-κB is a family of transcription factors that form homo- and hetero-dimeric complexes. Of these, the p65/p50 heterodimer is the most important. NF-κB p65/p50 heterodimers are bound to IκBα and retained in the cytoplasm under resting conditions. Upon activation, IκBα is phosphorylated, leading to its degradation by the ubiquitin pathway. Once released from IκBα, NF-κB heterodimers translocate to the nucleus and bind to DNA motifs, thereby activating gene transcription. NF-κB is expressed in
Role of Bcl-2 family members
Pro-apoptotic (Bax, Bak and Bid) and anti-apoptotic (Bcl-2, Bcl-xL, A1 and myeloid-cell leukaemia sequence 1 [Mcl-1]) Bcl-2 family members are critical in regulating survival by affecting mitochondrial integrity (Figure 1). Enhanced expression of anti-apoptotic Bcl-2 family members, but not pro-apoptotic members, has been implicated in the pathogenesis of RA. Bcl-2 is more highly expressed in synovial tissue in RA than in OA, particularly in CD68− synovial fibroblasts [25]. In vitro, infecting
PI3K/Akt-1 pathway
Stimulation of the phosphatidylinositol 3-kinase (PI3K) pathway leads to activation of Akt-1, which can promote resistance to apoptosis by several mechanisms. Akt-1 is a serine/threonine kinase that regulates gene expression by phosphorylating and activating transcription factors, such as CREB (c-AMP response element binding protein). Akt-1 can inhibit apoptosis by phosphorylating BAD (Bcl-2-antagonist of cell death), by maintaining mitochondrial integrity, and by down-regulating expression of
Role of STAT3
High levels of IL-6 are present in the RA joint. Signal transducer and activator of transcription-3 (STAT3), a downstream target of IL-6, is constitutively activated in synovial tissue of RA patients, and is associated with a reduction in SOCS3, a repressor of cytokine signaling [33••]. Furthermore, in a collagen-induced arthritis model of RA, the expression of a dominant-negative STAT3 or SOCS3 resulted in amelioration of arthritis and a reduction of IL-6 and TNFα within the joints [33••].
Role of p53
The tumour suppressor molecule p53, which is important in apoptosis and cell-cycle control, is upregulated in the RA joint [35]. Earlier studies demonstrated that in RA synovial tissue some of the p53 was mutated, and that the observed mutations were capable of acting as dominant-negatives, inhibiting the function of wild-type p53 [36]. To define the location and extent of p53 mutations in RA, microdissected synovial tissue was examined [37••]. Clusters of p53 mutations were located mainly in
Enhanced apoptosis and anemia in RA
Anemia of chronic disease (ACD) is very common in patients with active RA. Examination of bone-marrow from patients with RA and ACD demonstrated a functional haematopoietic progenitor defect, reduced numbers of CD34+ progenitor cells, increased apoptotic CD34+ cells, increased CD34+ cells, increased FasL+ cells, and increased TNFα in the supernatants from cultured cells 40.••, 41.•. Following treatment with an anti-TNFα antibody (infliximamb), these abnormalities were reversed 40.••, 41.•.
Conclusions
Although Fas and FasL are highly expressed on synovial lining macrophages, which are in intimate contact with each other and with synovial fibroblasts, insufficient apoptosis is observed to result in disease remission. Observations in experimental animals and in patients with RA suggest that enhanced apoptosis could be therapeutically beneficial. This paucity of apoptosis within the joint might be the result of a variety of mechanisms, including the presence of Flip, which is highly expressed
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
Richard M Pope’s work was supported by awards from the National Institute of Health (N01-AR62221 and 1R01 AR049217), and The Veterans Administration Research Service (Merit Review) from the National and the Greater Chicagoland Chapters of The Arthritis Foundation. We thank Yingyu Ma for the preparation of the figure in the text.
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