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• W3020155384 abstract "Purpose: Osteoarthritis (OA) is a low-grade inflammatory disease where the imbalance between catabolic and anabolic processes results in gradual degradation of the cartilage. Today there are no registered disease modifying drugs able to inhibit or prevent the disease and the diagnosis is based on radiological techniques which only detect structural changes that occur late in the disease process. Pharmaceutical interventions should not only focus on pain inhibition, but rather be disease modifying and stop the deleterious cartilage degradation. It is therefore of utmost importance to find drugs or natural molecular substances that inhibit the disease progression. Several studies have suggested a link between vitamin D status and OA; some have found that individuals deficient in vitamin D have an increased risk of progressive knee-osteoarthritis, and there are reports of a pain reducing effect from oral supplementation. Vitamin D has been detected in the synovial fluid, and beyond that, the vitamin D receptor has been discovered in the less differentiated, superficially located chondrocytes. The aim of this study was to investigate the effect of vitamin D treatment of osteoarthritic chondrocytes. For that purpose, we needed to choose suitable cells that would phenotypically resemble chondrocytes superficially located in the cartilage. One way to achieve this is by culturing osteoarthritic chondrocytes in monolayer, or, by differentiating iPSCs to chondroprogenitor cells. Our initial strategy was to investigate the impact of vitamin D on the expression of genes that regulate cartilage catabolism, anabolism, apoptosis, proliferation and pain perception. Methods: Chondrocytes were harvested from patients undergoing autologous chondrocyte implantation (ACI) of the knee. The macroscopically classification of the joint was cartilage having mild structural changes. Chondrocytes grown in 2D culture were treated with vitamin D3 for 1 day at concentrations of between 0 and 1 mM (untreated cells were used as control). The cells were then immediately collected for RNA isolation. Lysis of the cellular constructs was performed with RLT buffer from the Qiagen Mini-Kit. The RNA concentration and quality were obtained immediately after extraction using the NanoDrop 2000 (Thermo Fisher). The cDNA was prepared from total RNA using a High-Capacity cDNA Reverse Transcriptase Kit with random hexamers and RNase Inhibitor on a 2720 Thermal Cycler. Subsequent Real-time quantitative polymerase-chain-reaction (qPCR) was performed using TaqMan Gene Expression Master Mix in combination with different TaqMan gene expression assays. All samples were analyzed in duplicate on the 7900HT instrument. The expressions of the vitamin D receptor (VDR), GDF-5, ADAMTS-4, MMP-13, TIMP1, TIMP2, TIMP3, Bcl-2, FGF-18, Ki-67, NGF, TrkA and p75 and were analyzed. At least 8 patients were analyzed for each gene. Furthermore, iPSCs were forced to differentiate to chondroprogenitors under the influence of specific growth factors and small molecules and with the help of 3D cultivation. At 6 different times, some cells were collected for RNA isolation and qPCR analysis. So far, 1 patient has been analyzed. Results: In OA chondrocytes stimulated with vitamin D, a significant downregulation of the gene expressions of the catabolic proteases ADAMTS-4 and MMP-13 was shown. In addition, vitamin D significantly stimulated anabolic processes, and caused increased gene expressions of GDF-5, TIMP1, TIMP2, TIMP3 and FGF-18. Furthermore, vitamin D upregulated Bcl-2, an anti-apoptotic protein as well as Ki-67, a proliferation marker. In differentiated iPSCs, GDF-5 and VDR were expressed, as well as collagen II, Sox 9 and aggrecan, which means that these cells truly represented a pool of (pre-)chondrocytes. In line with clinical studies showing pain-relieving effect of vitamin D, vitamin D downregulated NGF and TrkA. Furthermore, in differentiated iPSCs, vitamin D caused a robust increase in gene expression of GDF-5, and also, a small but robust increase in expression of Bcl-2 and FGF18, at all times analyzed during the differentiation process. The gene expressions of MMP-13 and ADAMTS-4 were very low in these cells and therefore not statistically significant. Conclusions: Vitamin D may prevent degradation of certain matrix molecules by downregulating the aggrecan-specific proteinase ADAMTS-4 and collagen-specific proteinase MMP-13 and also, by upregulating TIMP-1, TIMP-2 and TIMP-3, inhibitors of ADAMTs and MMPs in chondrocytes from knee with cartilage injuries. Furthermore, vitamin D may inhibit apoptosis genes. In addition, mediators of pain perception, like NGF and TrkA, may be targeted by vitamin D transcriptional repression activity. In conclusion, vitamin D exert disease modifying effects on gene levels in vitro." @default.
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• W3020155384 date "2020-04-01" @default.
• W3020155384 modified "2023-10-18" @default.
• W3020155384 title "Vitamin D exerts disease modifying effects on oa chondrocytes and differentiated IPSCS in vitro" @default.
• W3020155384 doi "https://doi.org/10.1016/j.joca.2020.02.159" @default.
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