The Role of Apoptosis in Arthritis

Abstract

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 Sjögren's syndrome causes gland destruction by apoptosis with resultant gland dysfunction.

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…Bcl-2 is another of the anti-apoptosis proteins [10][11][12]. Bcl-2 forms heterodimers with Bak, Bax and Bcl-(x)L. These proteins and their interactions with one another are so important to an understanding of apoptosis resistance that studies have been undertaken to determine the extent to which inhibitors of Bcl-2, and Bcl-x(L) [66] may have therapeutic efficacy in RA among other autoimmune disorders.…”

“…Fas (CD95)/Fas ligand (FasL; CD178)-induced signaling is a prominent apoptosis pathway in many cell types [10][11][12]. FasL synthesized predominately by activated T-cells is a homotrimeric membrane-bound molecule with the capacity to bind 3 Fas receptor molecules on the surface of target cells.…”

“…The majority of these studies showed that methotrexate (MTX) and leflunomide were able to induce apoptosis in vitro in a variety 1 c-kit tyrosine kinase is a mast/stem cell growth factor receptor also known as CD117 [131] 2 ZAP-70, ζ-chain-associated protein-70 and a member of the tyrosine kinase family that is normally expressed by T-cells and natural killer cells [132] 3 SIRT1 is silent mating type information regulation 2 homolog (sirtuin-1) and a deacetylating enzyme [133] 4 PAR-2, Protease-activated receptor-2 and a subfamily member related to G-protein coupled receptors that may be activated by cleavage through their extracellular domain [134] 5 NF-AT5, Nuclear factor of activated T-cells 5 belonging to the NFAT family of transcription factors [135] 6 Human umbilical vascular endothelial cells 7 Mcl-1, Induced myeloid leukemia cell differentiation protein [136] 8 Epigallocatechin-3-gallate 9 MDC, myeloid-derived cells; PDC, plasmacytoid-derived cells 10 Apaf-1, Apoptotic protease activating factor-1 11 An inhibitor of geranylgeranyl transferase [137] 12 An inhibitor of RhoA kinase [138] 1 REL1096 is the p65 (Rel A) subunit of NF-κB 2 GADD45β is the growth arrest and DNA-damage-inducible45β protein [148] 3 Putative consensus sites for the binding of miR-124a and miR-146a to the 3'-untranslated regions of cyclin-dependent kinase-2 (CDK-2) and MCP-1, respectively 4 Putative consensus site for the binding of miR-146a to the 3' untranslated region of Fas-associated factor-1 of cells pertinent to RA pathology as well as cells involved in generalized inflammation, including, T-cells, neutrophils, mast cells and macrophages. By contrast, although NSAIDS were proposed as potential apoptosis inducers [166], the NSAID, celecoxib, failed to induce apoptosis in RAFLS in vitro [171].…”

“…However, in certain pathologic conditions such as RA, 'apoptosis resistance' is a cardinal characteristic of RA synovial tissue [10]. Indeed, many of the commonly employed drug therapies in use for treating RA clinical activity are based, in part, on restoring a balance between synoviocyte proliferation and synoviocyte apoptosis [10][11][12][13] as well as diminishing the negative effects of autoreactive T-and B-lymphocytes and antigen-presenting cells to the RA process [14]. This paper will focus on the most recent developments since 2004 in our understanding of the fundamental mechanisms underlying defective apoptosis among the cells of RA synovial tissue with the inclusion of selected papers prior to 2004 to address the field from an historical perspective.…”

Gene Therapy Outcomes in Experimental Models of Inflammatory Arthritis

“…In addition, because new blood vessel formation is also intimately involved with perpetuating the chronic state of inflammation associated with RA, experimental gene therapy strategies designed to suppress the activity of pro-angiogenesis factors such as vascular endothelial growth factor (VEGF) (Afuwape et al, 2003) and Tie-2 (Chen et al, 2005) have also been earnestly pursued. There also exists an elevated frequency of apoptotic cells in RA articular cartilage joints which is likely to contribute to diminished chondrocyte vitality (Malemud & Gillespie, 2005). By contrast, resistance to induction of apoptosis in RA synovial-like fibroblasts (Hutcheson & Perlman, 2008) and up-regulation of chemokines and adhesion molecules (Malemud & Reddy, 2008) are generally considered to be hallmarks of synovial tissue hyperplasia.…”