Charles J. Malemud and Heather J. Gillespie Pages 131 - 142 ( 12 )
Programmed cell death (i.e. apoptosis) plays a critical role in the pathogenesis and progression of several arthritic conditions and autoimmune disorders. Apoptosis induction is dependent on the extent to which the initiating apoptotic signal occurs via a receptor-mediated event (i.e. extrinsic pathway) or by changes in mitochondrial membrane permeability (i.e. intrinsic pathway). In this regard, differential activation of downstream caspases that degrade chromatin-containing DNA resulting in internucleosomal DNA fragmentation occurs by one of these apoptosis pathways or by combinations of both. In degenerative joint diseases such as osteoarthritis, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) as well as nitric oxide (NO) levels are significantly elevated in osteoarthritic joint synovial fluid. Thus, IL-1, TNF-α as well as NO induced human chondrocyte apoptosis in vitro and apoptosis frequency is often elevated in aging and osteoarthritic cartilage compared to young normal subjects or cartilage age-matched to the osteoarthritic specimens, respectively. A decrease in viable chondrocytes which could result from apoptosis induction in articular cartilage probably has significant implications for cartilage repair in osteoarthritis. Synovial hyperplasia with the resultant formation of pannus suggests that apoptosis-resistance pathways are active in rheumatoid arthritis. A resistance to apoptosis induction is pertinent to cartilage and bone destruction as well in rheumatoid arthritis as is the severity and progression of rheumatoid arthritis pathology. It is noteworthy that medical management of rheumatoid or psoriatic arthritis with anti-TNF-α monoclonal antibodies, while limiting lymphocyte infiltration into affected tissues does not induce apoptosis in synovial joint tissue. Systemic lupus erythematosus is an autoimmune disorder in which the failure to delete auto-reactive Tlymphocytes during immune development suggests that dysfunctional T-lymphocyte function may result from defective apoptosis. Defective T lymphocytes are responsible for abnormal B-cell function, autoantibody production as well as synovial joint arthropathy in lupus. In another view, lupus may be characterized by overly aggressive apoptosis leading to increased apoptotic cell load coupled to a deficiency in apoptotic cell clearance. Lymphocyte infiltration of salivary and lacrimal glands characteristic of Sjorens syndrome causes glagnd destruction by apoptosis with resultant gland dysfunction.
apoptosis, arthritis, cytokines, extracellular signal-regulated kinases, protein kinases, nuclear factor-kappab, t-lymphocyte activation
Case Western Reserve University, Department of Medicine/Division of Rheumatic Diseases, University Hospitals of Cleveland, 2061 Cornell Road, Room 207, Cleveland, Ohio 44106-5076, USA.