Impact of ionizing radiation on adipokine-induced inflammation in musculoskeletal diseases (MSD): Investigations in primary cells and MSD patients

Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common musculoskeletal diseases (MSD) that affect the joints. Both diseases are characterized by the destructive changes of articular cartilage and bone, accompanied by increasing disability and pain. Despite the differences in the development of RA and OA, the inflammation process plays a decisive role in both cases. The key players in RA are synovial fibroblasts, which gain an aggressive behaviour and pro-inflammatory phenotype in the course of disease. The production of different pro-inflammatory cytokines and matrix-degrading enzymes by synovial cells not only triggers the destruction of cartilage and activation of bone-resorbing osteoclasts, but also sustain the activation status of rheumatoid arthritis synovial fibroblasts (RASF), contributing to the perpetuation of inflammation in arthritic joint. Besides cytokines, the adipokines, mostly produced by adipose tissue, are known to induce the expression of pro-inflammatory cytokines in RASF. Chronic inflammatory diseases are usually treated with anti-inflammatory drugs. Besides medications, an additional pain relief is achieved by the treatment of patients with low-dose ionizing radiation, either as local photon irradiation or whole-body exposure to radon in radon baths or galleries. The anti-inflammatory effects of radon are used in the therapy of MSD since many years; however, the underlying cellular and molecular mechanisms are widely unknown. Therefore, within the scope of this thesis, the effect of a serial radon-bath treatment on adipokine serum levels in MSD patients was investigated (RAD-ON01 study). In addition, it was examined whether X-ray radiation affects the ability of adipocytes to produce adipokines or influences the response of synovial fibroblasts to adipokines, leading to the attenuation of inflammation in arthritic joint. In the present work, a significant decrease of adipokine visfatin in the serum of MSD patients after serial radon-bath treatment is shown for the first time. Furthermore, the positive correlation between visfatin serum levels and pain duration as well as pain intensity was determined, indicating an attenuation of inflammation. In addition, results obtained in vitro demonstrated the ability of X-ray radiation to reduce adipokine-induced production of pro-inflammatory and matrix-degrading factors (IL-6, MCP-1, MMP-1) by rheumatoid arthritis synovial fibroblasts, potentially inhibiting inflammation. Furthermore, the results of the present work showed that X-ray irradiation does not affect the differentiation process of adipocytes in vitro and their ability to produce adipokines, irrespective of the dose, indicating a radiation-resistant phenotype of adipose cells. In addition, the obtained results revealed that mature adipocytes are not the main source of adipokines in the arthritic joint. Taken together, the results obtained in vitro are consistent with those obtained in vivo, indicating that ionizing radiation may affect the inflammation process in joints of MSD patients. The findings of this work contribute to a better understanding of cellular and molecular mechanisms related to the low-dose radio- (LD-RT) and radon therapy.