Molecular and cellular basis of rheumatoid joint destruction

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

“…Several studies have suggested that genetic and environmental factors can trigger joint inflammation (14,15). Using a novel technique, we have recently demonstrated the hypoxic nature of synovial tissue in inflammatory arthritis, and we reported that in vivo synovial tissue partial oxygen pressure (tPO 2 ) measurements were strongly associated with levels of joint inflammation, vascularity, blood vessel stability, and disease activity (16,17).…”

Different expression levels of TNF receptors on the rheumatoid synovial macrophages derived from surgery and a synovectomy as detected by a new flow cytometric analysis

“…Rheumatoid synovial tissue contains macrophagelike cells (type A), fibroblast-like cells (type B), dendritic-like cells, and infiltrated lymphocytes, demonstrating that these heterogeneous cells would constitute the RA inflammatory synovium (Feldmann et al 1996b;Karouzakis et al 2006;Muller-Ladner et al 2007). We previously reported apoptosis (Kawakami et al 1999Miyashita et al 2003Miyashita et al , 2004Tamai et al 2006), cell differentiation ), cell proliferation (Eguchi et al 1992;Migita et al 2000Migita et al , 2001, signal transduction (Yamasaki et al , 2002, sensitivity to drugs , and protein expression of the rheumatoid synovial cells Tanaka et al 2004) using the long-time cultured synovial cells derived from the knee joint replacement surgery.…”

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…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].…”

“…Aberrant proliferation and survival of activated T-and B-lymphocytes, mast cells, neutrophils, macrophages and accessory antigen-presenting cells, (i.e. dendritic cells; DC) is a key component of RA pathophysiology [4,5]. In part, our understanding of this scenario includes the fact that these cells are attracted to, and retained within synovial joint tissues, as a result of the over-expression of chemokines and adhesion molecules [6].…”

“…Most prominent among these pro-inflammatory cytokines are tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) as well as IL-6, IL-7, IL-8, IL-12/IL-23, IL-15, IL-17, IL-18, IL-32, interferon-γ and growth factors, including, fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF), the latter produced principally by T-and B-lymphocytes and macrophages. The combination of these cytokines and growth factors cause a dysregulation of synoviocyte proliferation that lead to the development of synovial tissue hyperplasia [4,[6][7][8][9].…”