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Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools.

Vitamin D analogue calcipotriol is currently used in the local treatment of psoriasis. However, it also has antiproliferative and anti-inflammatory effects in the cells of the joint — suggesting a possible benefit in local treatment of arthritis. In this study, calcipotriol was studied in different in vitro methods to find out its effect on synovial and mesenchymal stromal cells. Primary human cell lines of osteoarthritis or rheumatoid arthritis patients (five mesenchymal stromal cells, MSC, and four synovial stromal cells, SSC) were cultured to study migration and proliferation of the cells in a wound healing model. The media was supplemented with calcipotriol, 1,25(OH)2D3, dexamethasone, betamethasone, methylprednisolone or control solution in 1–100 nM concentrations. To see possible toxic effects of calcipotriol, concentrations up to 10 µM in SSCs and MSCs were studied in apoptosis and necrosis assays in four cell lines. Calcipotriol and 1,25(OH)₂D₃, as well as the three glucocorticoids, reduced the migration of both SSCs and MSCs. In SSCs, the effect of calcipotriol and 1,25(OH)₂D₃ was at least as effective as with glucocorticoids, while with MSCs, the glucocorticoids were stronger inhibitors of migration. The antimigratory of calcipotriol and 1,25(OH)₂D₃ was consistently maintained in 10 µM and 1 µM. Calcipotriol was not toxic to MSCs and SSCs up to concentrations of 10 µM. Calcipotriol, as well as 1,25(OH)₂D₃, exerts antimigratory and antiproliferative effects on human SSCs and MSCs of the joint. These effects are not caused by apoptosis or necrosis. Both calcipotriol and 1,25(OH)₂D₃ have similar effects as glucocorticoids without apparent toxicity, suggesting that calcipotriol might be an eligible candidate to the local treatment of arthritis with a broad therapeutic window.

Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are common joint diseases associated with changes in local, as well as systemic bone structure and osteoclast function. We investigated how the different soluble inflammatory stimuli in these diseases can affect osteoclastogenesis and bone resorption in vitro. Methods: Human peripheral blood mononuclear cell-derived osteoclasts were cultured on bone slices with serum from treatment-naïve RA patients and healthy controls and with synovial fluid samples acquired from RA and OA patients. The concentrations of 29 different cytokines and related proteins, including RANKL and OPG, were analyzed in the fluids tested. Results: RA serum and synovial fluid increased both osteoclastogenesis and bone resorption. Osteoclastogenesis and activity increased more in the cultures containing OA than RA synovial fluid. The osteoclasts cultured in different culture media exhibited different phenotypes, especially the cells cultured with OA synovial fluid were generally larger and had more nuclei. A general increase in proinflammatory cytokines in RA synovial fluid and serum was found. Surprisingly, OA synovial fluid showed lower levels of osteoclastogenesis inhibiting cytokines, such as IL-4 and IL-10, than RA synovial fluid, which at least partly explains more pronounced osteoclastogenesis. No significant difference was found in RANKL or OPG levels. Conclusions: The proinflammatory stimulus in OA and RA drives the monocyte differentiation towards inflammatory osteoclastogenesis and altered osteoclast phenotype.

Introduction: All animals, including humans, are exposed to heavy metals which are known to accumulate in different tissues, especially in bone. During pregnancy, the maternal bone turnover is increased and the metals in the mother’s body can be mobilized into the bloodstream. Heavy metals in maternal blood are known to pass through the placenta to the fetal blood and finally, deposited to bone tissue. However, there are no studies on the concentration of metals in the fetal solid tissues and until now, the rate of metal transfer from mother to fetus is not exactly known. Materials and methods: Samples of the blood, liver, placenta, and three different bones were collected from 17 pregnant ewes and their 27 fetuses. The animals had no known exposure to heavy metals. The concentrations of Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, P, Pb, Rb, Sb, Sn, Sr, Te, Ti, Tl, V, and Zn were analyzed using ICP-MS. Results and discussion: The concentration of Sb, Sn, Te, and Tl were under the detection limit in all the samples. The other metals were found in all maternal and fetal tissues, suggesting that all detectable metals cross the placenta. Blood concentrations were low compared to solid tissue concentrations. The concentrations of essential elements varied between maternal and fetal tissues, which could be explained by biological differences. The differences in concentrations of non-essential elements between the ewe and fetuses were smaller. The most significant differences were between maternal and fetal concentrations of Ba and Sr, which is at least partly explained by the mineralization degree of the bone. Conclusion: Heavy metals accumulate in fetal solid tissues in sheep that are not directly exposed to heavy metals. Because of the differences in anatomy between human and sheep placenta, the accumulation in the tissue of human fetuses should be extrapolated cautiously. However, there might be some clinical relevance for fertile aged women

Background: Modern metal-on-metal (MOM) arthroplasties were performed for over a decade before alarming reports of adverse metal reactions dramatically reduced their use. Failures are seen more often with high-wearing implants, but also well-positioned components with more favourable wear patterns can cause problems. There are no specific clinical indicators that could help us to predict the prognosis of these implants. For this reason, we still need more information on the effect of underlying factors that contribute to this process. Methods: In this prospective cohort study, we investigated how cup orientation and type of pseudotumour determined by the Hart classification effect the distribution of metals in blood, synovial fluid and tissues surrounding the metal-on-metal hip prosthesis in revision surgery patients. One thousand two hundred twenty-nine metal-on-metal hip patients were screened and of those, 60 patients that had a revision surgery due to adverse metal reaction were included. Whole blood, synovial fluid and synovial/pseudotumour tissue samples were analysed for metal ion concentrations (Co, Cr, Mo and Ti). Results: The lowest metal concentrations were found when both cup anteversion and inclination were optimal, and the highest when both were suboptimal. Suboptimal anteversion alone raised Cr-ion concentrations more than suboptimal inclination. The concentrations of metals in blood, synovial fluid or synovial soft tissue were the same in patients with and without a pseudotumour, but the relative transfer percentage of cobalt from synovial fluid to blood was higher in patients with a pseudotumour. Conclusions: The implant orientation alone does not explain the metal concentrations found in tissues or distribution of metals between different tissues. The accumulation of metals in periprosthetic soft tissues increase the total metal load, and in the presence of a pseudotumour this is reflected in the transfer ratio of Co from synovial fluid to