geranylgeranylacetone and Arthritis--Rheumatoid

Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-κB ligand (RANKL), TNF-α, IL-6, IL-17, and IFN-γ. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in regulating bone resorption. In 2009, we demonstrated that novel peptides from T-cell leukemia translocation-associated gene (TCTA) protein expressed in synovial tissues from patients with RA inhibit human osteoclastogenesis, preventing cellular fusion via the interaction between TCTA protein and a putative counterpart molecule. Only a few studies on the role of TCTA protein have been reported. Genomic Southern blots demonstrated a reduced TCTA signal in three of four small cell lung cancer cell lines, suggesting the loss of one of the two copies of the gene. In the current paper, we reviewed the roles of TCTA protein in lung cancer cell lines and human osteoclastogenesis.

Topics: Animals; Arthritis, Rheumatoid; Cell Proliferation; Cytokines; Diterpenes; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Macrophages; Mice; Models, Biological; Osteoclasts; Peptides; Proteins; RANK Ligand; Synovial Membrane

Biologic therapies including tumor necrosis factor alpha (TNF-alpha)-blocking therapy have been shown to reduce disease activity measures and joint damage progression. However, effects of biologic therapies on systemic osteoporosis remain to be elucidated in patients with rheumatoid arthritis (RA). In this review article, we reviewed the literature on the issue after we described our hypothesis on the pathogenesis of synovitis in patients with RA.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Denosumab; Diterpenes; Drug Design; Humans; Infliximab; Interleukin-1; Interleukin-17; Interleukin-6; Osteoclasts; Osteoporosis; RANK Ligand; Receptors, Interleukin-6; Tumor Necrosis Factor-alpha

Fluvastatin (Fluv) is reported to induce apoptosis in rheumatoid arthritis (RA) synoviocytes through the blocking of protein geranylgeranylation. We report here our investigation of whether geranylgeranylacetone (GGA) induces cell death in RA synoviocytes. Synovial tissues were obtained from patients with RA at the time of total knee arthroplasty. Fibroblast-like synoviocytes (FLS) cultured in three passages were used for the experiments. The FLS were then cultured for 48 h in 48-well flat-bottomed plates containing various concentrations of GGA (0.1-4.0 microg/ml) and either 0.1 or 0.5 microM Fluv. We also examined the effect of GGA and Fluv in human fibroblasts from normal skin (CCD-25SK) and FLS from patients with osteoarthritis (OA). Cells demonstrating cell death were counted following trypan blue staining. In the absence of GGA, there was no apparent cell death, as evidence by trypan blue staining. Concentrations of GGA between 0.1 and 4.0 microg/ml induced cell death in RA FLS, but not in skin fibroblasts (CCD-25SK) nor OA FLS. The number of synoviocytes demonstrating cell death induced by 0.1 or 0.5 microM Fluv was significantly higher than that by the medium alone. In summary, we found that GGA induced cell death in RA FLS, suggesting that GGA may be a potential new therapeutic agent for RA as well as osteoporosis.

Topics: Anti-Ulcer Agents; Arthritis, Rheumatoid; Cell Death; Cells, Cultured; Diterpenes; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fibroblasts; Fluvastatin; Humans; Indoles; Synovial Membrane; Trypan Blue