The impact of serial radon and hyperthermia exposure in a therapeutic adit on pivotal cytokines of bone metabolism in rheumatoid arthritis and osteoarthritis.

Secondary osteoporosis is a frequent complication of rheumatoid arthritis (RA) and the result of an imbalance of catabolic and anabolic mechanisms of bone metabolism. The effects of serial low-dose radon and hyperthermia (LDRnHT) exposure in a therapeutic adit (12 applications in 3 weeks) on the serum levels of the cytokines osteoprotegerin (OPG), receptor activator of NF kappa-B ligand (RANKL), tumor necrosis factor-α (TNF-α), and also on the RANKL/OPG ratio were investigated in 25 RA patients and an age-matched control of 24 patients with osteoarthritis (OA). Cytokine measurements were performed at baseline and after completion of LDRnHT. Anti-CCP antibodies (ACPA) were measured in RA patients in parallel. Medication in both groups was limited to non-steroidal anti-inflammatory drugs, and low-dose prednisolone (16 of 24 RA patients) as needed. RA and OA patients showed a significant decrease of TNF-α levels (p < 0.001). Both groups showed significantly decreased levels of RANKL (RA: p < 0.001, OA: p < 0.01). Only the RA patients presented a significant increase of OPG (p < 0.01) and decrease of the RANKL/OPG ratio (p < 0.01), and the ACPA levels (p < 0.001). LDRnHT results in a reduction of osteocatabolic and an increase of osteoanabolic cytokines, which represents the molecular basis for inhibiting osteoclastic activity in secondary osteoporosis and explains in part the effect of LDRnHT this physical therapy modality in a key inflammatory disease. Although reduced ACPA levels were observed under the therapy and although this could potentially contribute to an osteoprotective effect, in this case, it is rather uncertain as the reduction was only minor in magnitude.

The effect of mild whole-body hyperthermia on systemic levels of TNF-alpha, IL-1beta, and IL-6 in patients with ankylosing spondylitis.

Serial mild whole-body hyperthermia is a widely used balneotherapy modality for clinically inactive ankylosing spondylitis (AS) in rehabilitative medicine. Thus far, the mechanisms of its favorable influence on the symptoms of AS are not completely understood. We therefore analyzed the effect of mild whole-body hyperthermia on the systemic levels of pivotal proinflammatory cytokines. Twelve male subjects with AS and 12 healthy control subjects received nine cycles of whole-body hyperthermia (target body core temperature, 38.5 degrees C; duration, 50 min). Serum samples were taken at the beginning of the last cycle and at 1, 6, and 24 h for measurement of tumor necrosis factor alpha, interleukin 1beta and interleukin 6. Significant differences of cytokine levels were found between both groups. In AS patients, hyperthermia caused a significant reduction of all cytokines by 40-50%. Thus, serial mild whole-body hyperthermia in AS results in heat-induced changes of the proinflammatory cytokine network.

The potential of adiponectin in driving arthritis.

Articular adipose tissue is a ubiquitous component of human joints, but its local functions are largely unknown. Because recent studies revealed several links between adipose tissue, adipocytokines, and arthritis, we investigated the expression of the adipocytokine adiponectin and its functional role in articular adipose tissue and synovium of patients with different arthritides. In contrast to its protective role in endocrinological and vascular diseases, adiponectin was found to be involved in key pathways of inflammation and matrix degradation in the human joint. The effects of adiponectin in human synovial fibroblasts appear to be highly selective by inducing only two of the main mediators of rheumatoid arthritis pathophysiology, IL-6 and matrix metalloproteinase-1, via the p38 MAPK pathway. Owing to the observation that these effects could be inhibited by different TNF-alpha inhibitors, adipocytokines such as adiponectin may also be key targets for therapeutic strategies in inflammatory joint diseases. In summary, articular adipose tissue and adipocytokines cannot be regarded as innocent bystanders any more in chronic inflammatory diseases such as arthritis.

Evaluation of differentially expressed genes by a combination of cDNA array and RAP-PCR using the AtlasImage 2.0 software.

Evaluation of genes regulated differentially is essential for the development of therapeutic approaches in multifactorial diseases. To characterize gene expression profiles in multifactorial inflammatory and malignant diseases such as rheumatoid arthritis (RA) or colon adenoma (CA), RNA arbitrarily primed PCR (RAP-PCR) combined with cDNA array hybridization were performed and evaluated using an array-specific software.RNA of synovial fibroblasts from patients with RA and osteoarthritis (OA), and laser microdissected normal and colon adenoma tissue was used. RAP-PCR reactions were hybridized to cDNA array membranes. Arrays were analyzed by phosphor imaging, and the AtlasImage 2.0 software with different normalization settings. The AtlasImage 2.0 software was a useful tool to evaluate differentially expressed genes. However, software settings were needed to be optimized for every experimental approach and should be used without changes for all experiments. To compare RA vs. OA synovial fibroblasts and normal vs. CA expression patterns, global normalization using the sum method is recommended.