Musculoskeletal disorders (MSDs) are the most frequent cause of disability in Europe. Reduced mobility and quality of life of the patients are often associated with pain due to chronic inflammation. The inflammatory process, accompanied by a destruction of the cartilage and bone tissue, is discussed as a result of (A) the infiltration of immune cells into the joints, (B) an altered homeostasis of the joint cavity (synovium) with a critical role of bone remodeling cells, and (C) release of inflammatory factors including adipokines in the arthritic joint. In addition to the classical medication, low-dose radiation therapy using photons or radon spa treatments has shown to reduce pain and improve the mobility of the patients. However, the cellular and molecular mechanisms of anti-inflammatory effects of radon are yet poorly understood. We analyzed blood and serum samples from 32 patients, suffering from MSDs, who had been treated in the radon spa in Bad Steben (Germany). Before and after therapy, we measured the levels of markers related to bone metabolism (collagen fragments type-1, cartilage oligomeric matrix protein, receptor activator of NFκB ligand, and osteoprotegerin) in the serum of patients. In addition, adipokines related to inflammation (visfatin, leptin, resistin, and adiponectin) were analyzed. Some of these factors are known to correlate with disease activity. Since T cells play an important role in the progression of the disease, we further analyzed in blood samples the frequency of pro- and anti-inflammatory T cell subpopulations (CD4+IL17+ T cells and CD4+FoxP3+ regulatory T cells). Overall, we found a decrease of collagen fragments (CTX-I), indicating decreased bone resorption, presumably by osteoclasts, in the serum of MSD patients. We also observed reduced levels of visfatin and a consistent trend toward an increase of regulatory T cells in the peripheral blood, both indicating attenuation of inflammation. However, key proteins of bone metabolism were unchanged on a systemic level, suggesting that these factors act locally after radon spa therapy of patients with MSDs.

Ionizing radiation generates DNA double-strand breaks (DSB) which, unless faithfully repaired, can generate chromosomal rearrangements in hematopoietic stem and/or progenitor cells (HSPC), potentially priming the cells towards a leukemic phenotype. Using an enhanced green fluorescent protein (EGFP)-based reporter system, we recently identified differences in the removal of enzyme-mediated DSB in human HSPC versus mature peripheral blood lymphocytes (PBL), particularly regarding homologous DSB repair (HR). Assessment of chromosomal breaks via premature chromosome condensation or γH2AX foci indicated similar efficiency and kinetics of radiation-induced DSB formation and rejoining in PBL and HSPC. Prolonged persistence of chromosomal breaks was observed for higher LET charged particles which are known to induce more complex DNA damage compared to X-rays. Consistent with HR deficiency in HSPC observed in our previous study, we noticed here pronounced focal accumulation of 53BP1 after X-ray and carbon ion exposure (intermediate LET) in HSPC versus PBL. For higher LET, 53BP1 foci kinetics was similarly delayed in PBL and HSPC suggesting similar failure to repair complex DNA damage. Data obtained with plasmid reporter systems revealed a dose- and LET-dependent HR increase after X-ray, carbon ion and higher LET exposure, particularly in HR-proficient immortalized and primary lymphocytes, confirming preferential use of conservative HR in PBL for intermediate LET damage repair. HR measured adjacent to the leukemia-associated MLL breakpoint cluster sequence in reporter lines revealed dose dependency of potentially leukemogenic rearrangements underscoring the risk of leukemia-induction by radiation treatment.

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Background and objectivesRheumatoid arthritis (RA) is a chronic inflammatory disease of the joints. For RA treatment, primarily drugs are used. However additional pain relieve is achieved when RA patients are treated either locally with low doses of sparsely ionising photons or by exposure to Radon. Main contributors to the inflammatory state in RA are adipokines, mainly produced by adipose tissue. To assess the effect of low radiation doses, we measured levels of adipokines in serum of patients with musculoskeletal diseases during Radon treatment. In additional in vitro experiments, we examined whether irradiation modifies the effects of recombinant adipokines on the expression of inflammatory and bone destructive factors in synovial fibroblasts (SF), key players in RA.Material and methodsSerum samples were collected from patients before and after treatment with radon baths. Adipokine levels were measured by ELISA. Human SF from RA patients (RASF) and healthy donors (NSF) were pretreated with adipokines for 24h prior to irradiation with X-rays, and cell supernatants were collected after 24h to measure inflammatory factors known to contribute to the inflammatory process in RA (IL-6, IL-8, MMP-1).ResultsIn the serum of patients, a significant decrease of the level of the adipokine visfatin was observed after therapy. The level of adiponectin was either reduced or unchanged, and no marked difference was observed for leptin. The results obtained in vitro using primary SF confirm the induction of proinflammatory factors by stimulation with adipokines. Irradiation of SF after treatment with adipokines, in turn, significantly reduces the expression of inflammatory factors.ConclusionOur data show for the first time a reduction of adipokine levels in serum of Radon treated patients. Since it is known that an elevated visfatin level positively correlates with serum levels of inflammatory factors IL-6 and CRP in RA patients, we hypothesise, that the decrease in serum visfatin level after low-dose irradiation affects the inflammatory process in the joint. Our in vitro results suggest the release of inflammatory factors after adipokine stimulation in both NSF and RASF can be reduced by low-dose X-ray irradiation, therefore potentially inhibiting inflammation in the joint of RA patients.

IntroductionRheumatoid arthritis (RA) and osteoarthritis (OA) are the most common musculoskeletal diseases (MSD) that affect the joints. Reduced mobility and quality of life are the consequences of the cartilage and bone tissue destruction and the chronic inflammation process, caused by release of bone destruction markers and inflammatory factors including adipokines in the joint. Besides medications, an additional pain relief is achieved by the treatment of patients with low-dose ionising radiation, either as local low-dose radiation therapy (LDRT) or whole-body exposure to radon in radon baths or galleries.ObjectivesIn the previous work we showed the decrease of serum levels of visfatin and serum carboxy-terminal collagen crosslinks of type-I collagen (CTX-I) in patients treated in radon baths.1 In the present study, we analysed serum samples of patients with MSD, who had been treated locally with photon radiation (LDRT). In addition, we analysed differentiation and activity of osteoclasts that were differentiated in vitro from patient-derived monocytes.MethodsSerum samples were collected from patients before and after treatment. Levels of visfatin and CTX-I were measured by ELISA. Monocytes were isolated from blood samples of patients and cultivated with M-CSF and RANKL on bone slices for 2 weeks. Osteoclasts were defined as TRAP and F-actin positive cells. TRAP activity was measured in the cell supernatants using TRAP Staining Kit.ResultsIn the serum of patients treated with LDRT, a trend to reduced concentration of CTX-I was observed directly after the therapy. Further, osteoclasts, differentiated in vitro from LDRT patient-derived monocytes, showed reduced TRAP activity.ConclusionsThe observations made in this study so far substantiate that the radiation-induced decrease of CTX-I levels could be one main factor that is related to the attenuation of inflammation and to the decrease of disease activity in the patients with MSD. This hypothesis is endorsed by the observed reduced differentiation and activity of in vitro cultivated patient-derived osteoclasts.Reference. Cucu Shreder, et al. Front. Immunol2017;8:882.AcknowledgementsThis work was supported by the German Federal Ministry of Education and Research (grant no. 02NUK017A and 02NUK017G, GREWIS), by Landesamt für Gesundheit und Lebensmittelsicherheit Bayern, and by Bayrisches Staatsbad Bad Steben GmbH.Disclosure of interestNone declared