Introduction
Osteoarthritis, OA, MSDs, stroke, pain, bone erosion, Rheumatoid arthritis, RA
MYOCARDIAL INFARCTION, OSTEOARTHRITIS, STROKE, DEGENERATIVE, GASTROINTESTINAL BLEEDING, DISORDERS, BONE EROSION, RHEUMATOID ARTHRITIS, ONCOLOGY, RITTER, MUSCULOSKELETAL DISORDER, INFLAMMATORY DISEASE
Edited by: Sumit Kumar Hira, University of Burdwan, IndiaReviewed by: Barbra Erickson, California State University, Fullerton, United StatesMarkus Ritter, Paracelsus Medical University, Austria†Present address: Felicitas Rapp, Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyMusculoskeletal disorders (MSDs) are associated with pain and lead to reduced mobility and quality of life for patients. Radon therapy is used as alternative or complementary to pharmaceutical treatments. According to previous reports, radon spa leads to analgesic and anti-inflammatory effects, but the cellular and molecular mechanisms are widely unknown. A previous study (RAD-ON01) revealed, that bone erosion markers like collagen fragments (C-terminal telopeptide, CTX) are reduced after radon spa treatment in serum of patients with degenerative MSDs. Within the scope of the prospective, placebo-controlled RAD-ON02 trial presented here, we analyzed the influence of radon and thermal spa treatment on osteoclastogenesis. From patient blood, we isolate monocytes, seeded them on bone slices and differentiated them in the presence of growth factors into mature osteoclasts (mOCs). Subsequent analysis showed a smaller fraction of mOCs after both treatments, which was even smaller after radon spa treatment. A significantly reduced resorbed area on bone slices reflects this result. Only after radon spa treatment, we detected in the serum of patients a significant decrease of receptor activator of NF-κB ligand (RANKL), which indicates reduced differentiation of OCs. However, other markers for bone resorption (CTX) and bone formation (OPG, OCN) were not altered after both treatments. Adipokines, such as visfatin and leptin that play a role in some MSD-types by affecting osteoclastogenesis, were not changed after both treatments. Further, also immune cells have an influence on osteoclastogenesis, by inhibiting and promoting terminal differentiation and activation of OCs, respectively. After radon treatment, the fraction of Treg cells was significantly increased, whereas Th17 cells were not altered. Overall, we observed that both treatments had an influence on osteoclastogenesis and bone resorption. Moreover, radon spa treatment affected the Treg cell population as well as the Th17/Treg ratio were affected, pointing toward a contribution of the immune system after radon spa. These data obtained from patients enrolled in the RAD-ON02 trial indicate that radon is not alone responsible for the effects on bone metabolism, even though they are more pronounced after radon compared to thermal spa treatment.Musculoskeletal disorders (MSDs) include degenerative and inflammatory diseases, such as Rheumatoid arthritis (RA), Osteoarthritis (OA) or Calcaneodynia. Bone degradation and/or destruction of joints structure are hallmarks of MSDs (Standard pharmaceutical treatment consists in administration of non-steroidal anti-inflammatory drugs (NSAID)/non-steroidal antirheumatics (NSARs) or biologicals. However, these treatments are associated with high costs and have negative side effects, such as gastrointestinal bleeding, myocardial infarction, and stroke (In healthy tissue, bone is undergoing continuous remodeling, especially by bone-forming osteoblasts (OBs), osteocytes and resorbing osteoclasts (OCs) (Mature OCs (mOCs) are multinucleated bone-resorbing cells derived from the monocyte/macrophage lineage by fusion of several precursor cells. The cytokines macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) are essential for the onset of differentiation. First, monocytes differentiate into pro-osteoclasts (pro-OCs) under the influence of M-CSF (An antagonist of RANKL is osteoprotegerin (OPG), a soluble decoy receptor released by osteoblasts. OPG binds RANKL and thus inhibits osteoclastogenesis, and is as such considered as a marker for bone formation (Immune cells, such as regulatory T cells (Treg) cells and T helper 17 (Th17) cells have an influence on osteoclastogenesis. Treg cells may have immune suppressive effects (Beside bone erosion, progressive destruction of articular cartilage is e.g. a characteristic of OA (In OA patients, the systemic levels of the adipokines visfatin and leptin are elevated, both produced mainly by adipocytes (In this study, we aimed to investigate whether the long-lasting pain reduction and lowered expression of bone erosion markers that were observed in our previous study (