Apoptotic Pathways in Synovial Fibroblasts
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Apoptotic Pathways in Synovial Fibroblasts
RA (Rheumatoid Arthritis) is a chronic inflammatory disease of unknown etiology affecting diarthrodial joints. Inflammation and hyperplasia of the synovium are the hallmarks of RA. The normal synovium is a delicate tissue lining the joint capsule; however, in RA, the synovium transforms into an aggressive, tumor-like structure called the pannus. It is believed that inflammation promotes hyperplasia in the synovium, but the underlying mechanisms for this are largely unknown (Ref.1). Macrophages are major components in the inflammatory cascade and are also important mediators of joint destruction in RA. Large numbers of macrophages are present in synovial tissue and their cell numbers are associated with scores for local disease activity in clinically involved joints of RA patients (Ref.2).

Macrophage activity in the synovial compartment includes the production of chemotactic cytokines called Chemokines. The proinflammatory cytokines trigger and fuel the chronic inflammatory process in the synovium by governing a variety of pathophysiological processes including cell activation, cell proliferation, tissue resorption and chemotaxis (Ref.3). In particular, TNF-Alpha (Tumor Necrosis Factor-Alpha), IL-1 (Interleukin-1) and GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) are major pathogenic mediators in RA, inducing and propagating a chronic inflammatory process in the synovial membrane. The human RA synovium contains a significant proportion of apoptotic cells, and elevated expression of TNF-Alpha protein and functional FasL (Fas Ligand) in the synovium is a common feature of RA (Ref.4). Several mechanisms promote the survival of synovial fibroblasts in the RA joint. After activation by TNF when monocytes migrate into the synovial tissue, expression of the anti-apoptotic molecule FLIP (FLICE Inhibitory Protein) is induced. FLIP binds to FADD (Fas-Associated via Death Domain) and inhibits the activation of Caspase8 after Fas ligation. FLIP can also confer resistance to Fas-mediated apoptosis to macrophages although other factors might contribute (Ref.5). Activation of both the NF-KappaB (Nuclear Factor-KappaB) and the PI3K (Phosphatidylinositol 3-Kinase)-Akt1 pathways protect against TNF-induced apoptosis. Activation of NF-KappaB in synoviocytes is required for the induction of inflammatory cytokines, including IL-1Beta, IL-6, and TNF-Alpha. On the other hand, the activation of NF-KappaB by inflammation inhibits TNF-Alpha and FasL-mediated apoptosis, thereby promoting hyperplasia. NF-KappaB is also required for mitogenic activity of GF (Growth Factors) in synovial fibroblasts, thus implicating NF-KappaB in the control of proliferation of the inflamed synovium. The PI3K pathway is crucial to protection against apoptosis by various mechanisms, including the activation of NF-KappaB, phosphorylation of BAD (BCL2-Antagonist of Cell Death), inhibition of Caspase9 and suppression of FasL. XIAP (X-linked Inhibitor of Apoptosis Protein) is also involved in the NF-KappaB pathway, although the mechanism that regulates the protection that is conferred through the PI3K-Akt1 pathway remains to be clarified. p53 is upregulated in RA synovial fibroblasts, which is induced by UV irradiation or DNA damage owing to chronic inflammation in the RA joint. Inactivating mutations in the expressed p53 are capable of suppressing the induction of apoptosis.

Synovial fibroblasts in rheumatoid synovium also contribute significantly to localized bone loss. These cells produce Chemokines such as MIP1 (Macrophage Inflammatory Peptide-1), regulated-upon-activation normal T-Cell expressed and secreted, IL-8, and IL-16, which promote lymphocyte infiltration and support lympho proliferation via secretion of various colony-stimulating factors (Ref.6). This results in a large pool of RANKL (Receptor Activator of NF-KappaB Ligand)-expressing lymphocytes supporting osteoclastogenesis and local bone loss. Furthermore, synovial fibroblasts may directly contribute to local bone destruction by expressing RANKL on their surface and by secreting cathepsins (Ref.7). As TNF and IL-1 are primarily the products of macrophages in the RA joint, a better understanding of the mechanisms that regulate the apoptosis of synovial macrophages might lead to more-effective therapies. The local inhibition of NF-KappaB or, perhaps, Akt1, combined with the TNF that is already present locally, might enhance the therapeutic potential of this approach, rendering both macrophages and synovial fibroblasts sensitive to apoptosis. Therapy to diminish the ingress of cells, by inducing the apoptosis of new blood vessels within the joint, is another approach that might be both selective and effective. A better understanding of the role of the adaptive immune system, as well as better insights into the mechanisms that prevent adequate apoptosis locally, should allow the development of more rational, long-lasting therapies that will benefit all patients with this disease.