Background Platelet‐rich‐plasma (PRP) is used to treat knee osteoarthritis; however, mechanistic evidence of PRP effectiveness for pain relief is limited. Objective To assess molecular biomarkers and mesenchymal stem cells (MSCs) in synovial fluid during PRP treatment of the osteoarthritic knee joint. Design Single blinded, randomized, placebo controlled pilot study. Setting Veterans Affairs Medical Center. Participants Seventeen participants with mild to moderate knee osteoarthritis were randomized in a 2:1 placebo‐controlled ratio, receiving PRP or saline (placebo) intra‐articular injection into the knee joint. Methods Knee synovial fluid was analyzed before the respective injections and again 10 days following injection. Participants were followed up to 12 months completing visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires at intervals over that period. Main Outcome Measures The effects of PRP on synovial protein and MSC gene expression levels were measured by multiplex enzyme‐linked immunosorbent assay and quantitative polymerase chain reaction. Results Novel biomarkers including levels of interleukin (IL)‐5, IL‐6, IL‐10, and tumor necrosis factor‐α were measured in synovial fluid 10 days after PRP treatment. Altered gene expression profiles in MSCs from patients treated with PRP were observed for matrix metalloproteinases and inflammatory markers (IL‐6, IL‐8, CCL2, TNF‐α). A2M protease was significantly increased following PRP treatment (P = .005). WOMAC scores declined for up to 3 months from baseline levels and remained low at 6 and 12 months in the PRP group. In contrast, WOMAC scores for patients receiving the saline injection were relatively unchanged for up to 12 months. Conclusions We report significant changes for the biomarker A2M (P = .005) as well as differences in expression of cellular markers and postulate that PRP modulates the local knee synovial environment by altering the inflammatory milieu, matrix degradation, and angiogenic growth factors. The PRP treatment group had less pain and stiffness and improved function scores.
Osteoarthritis (OA) is a common disabling disease worldwide, with no effective and safe disease-modifying drugs (DMOAD) in the market. However, studies suggest that drugs, such as liraglutide, which possess strong potential in decreasing low-grade systemic inflammation may be effective in treating OA. Therefore, the aim of this study was to examine the anti-inflammatory, analgesic, and anti-degradative effects in OA using in vitro and in vivo experiments. The results showed that intra-articular injection of liraglutide alleviated pain-related behavior in in vivo sodium monoiodoacetate OA mouse model, which was probably driven by the GLP-1R-mediated anti-inflammatory activity of liraglutide. Moreover, liraglutide treatment significantly decreased IL-6, PGE2 and nitric oxide secretion, and the expression of inflammatory genes in vitro in chondrocytes and macrophages in a dose-dependent manner. Additionally, liraglutide shifted polarized macrophage phenotype in vitro from the pro-inflammatory M1 phenotype to the M2 anti-inflammatory phenotype. Furthermore, liraglutide exerted anti-catabolic activity by significantly decreasing the activities of metalloproteinases and aggrecanases, a family of catabolic enzymes involved in cartilage breakdown in vitro. Overall, the findings of this study showed that liraglutide ameliorated OA-associated pain, possess anti-inflammatory and analgesic properties, and could constitute a novel therapeutic candidate for OA treatment.
Background:Osteoarthritis (OA) is an age-related joint disease which provokes chronic pain and limits mobility. The disease progression is associated with inflammatory responses and cartilage degradation. Both chondrocytes, the only cell type present in cartilage, and macrophages from the synovium, play a major role in OA pathophysiology. Liraglutide is a Glucagon-Like Peptide-1 Receptor (GLP-1R) agonist widely prescribed for the treatment of type 2 diabetes. Interestingly, anti-inflammatory properties of the GLP-1 pathway have been reported in various diseases outside diabetes.Objectives:We evaluated the anti-inflammatory and anti-catabolic effects of Liraglutide in two in vitro models relevant to OA by evaluating surrogate markers of inflammation, cartilage matrix proteolysis and differentiation.Methods:Lipopolysaccharide (LPS)-stimulated murine Raw 264.7 macrophages were treated with 10 concentrations (6.6nM-3.4µM) of Liraglutide for 24h. Anti-inflammatory activity was evaluated by the production of nitric oxide (NO) and prostaglandin E2 (PGE2) using Griess reaction and ELISA, respectively. Interleukin 1β (IL-1β)-stimulated mouse articular chondrocytes were treated with Liraglutide (6.6nM-3.4µM) for 24h. Production of IL-6, matrix metalloproteinase-3 (MMP-3) and glycosaminoglycans (GAG) was measured by ELISA and GAG assay, respectively. RTqPCR analyses were performed with three selected concentrations of Liraglutide (13.3nM, 53.1nM and 1.7µM) on both cell types to assess the expression of a panel of genes related to inflammation (IL-6, TNF, iNOS), M1/M2 macrophage phenotype (MCP-1, CD38, ERG-2), catabolism (MMP-13, ADAMTS-5) and differentiation (Sox9, Col2a1, Acan).Results:Liraglutide induced a dose-dependent inhibition of the LPS-induced production of NO (IC50=45nM) and PGE2 (IC50=54nM) in macrophages. Moreover, IL-6 and TNF gene expressions were significantly and dose-dependently decreased in Raw 264.7 cells treated with Liraglutide compared to LPS alone. Interestingly, there was a significant dose-dependent reduction of MCP-1 and CD38 (M1 marker) gene expression in cells treated with the 3 doses of Liraglutide compared to LPS alone while we observed a dose-dependent increase of ERG-2 (M2 marker) gene expression induced by Liraglutide. Liraglutide significantly dose-dependently reduced the IL-1β-induced release of IL-6 (IC50=38nM), MMP-3 (IC50=56nM) and GAG (IC50=47nM) in chondrocytes. Additionally, Liraglutide treatment dose-dependently decreased the IL-1β-induced gene expression of iNOS, MMP-13 and ADAMTS-5. Finally, IL-1β decreased gene expression of Sox9, Col2a1 and Acan differentiation markers, which was rescued in a dose-dependent manner by Liraglutide (Table 1).Table 1.Gene expression results (fold change) in Raw 264.7 murine macrophages or mouse primary articular chondrocytesCell typeMarkersVehicleVehicleLiraglutide (nM)13.353.11700Macrophages- LPS+ LPSIL61.0±0.2*63.6±7.158.8±6.536.3±8.4*30.8±2.6*TNFα1.0±0.2*26.8±4.917.5±2.6*9.5±1.8*4.1±2.1*MCP11.1±0.6*91.7±11.267.8±4.3*47.3±6.1*25.1±5.5*CD381.1±0.6*103.5±22.373.2±12.3*44.6±8.9*17.4±3.3*ERG21.0±0.3*0.3±0.11.1±0.5*2.1±0.6*3.1±0.2*Chondrocytes- IL1β+ IL1βiNOS1.0±0.2*47.8±17.634.2±15.518.9±8.2*11.8±2.9*MMP131.0±0.2*9.8±2.07.6±1.04.6±0.7*2.5±0.4*ADAMTS51.2±0.82.7±0.62.0±0.61.6±0.31.1±0.2Sox91.0±0.1*0.4±0.20.4±0.20.6±0.00.7±0.2Col2a11.0±0.2*0.3±0.10.3±0.10.5±0.30.8±0.3*Acan1.2±0.8*0.2±0.10.1±0.00.5±0.1*0.7±0.2** p<0.05 vs LPS or IL1β alone, n=4Conclusion:A shift in M1/M2 macrophage phenotype and the inhibition of chondrocyte expression of several mediators involved in inflammation and cartilage degradation explain, at least in part, our previous results from rodent osteoarthritis models that showed an analgesic, anti-inflammatory and anti-degradative effect of Liraglutide. The fact that Liraglutide is already safely prescribed in another indication allows us to foresee a first trial in humans in the short term.Acknowledgements:All the people who contributed to the InOsteo project: the members of 4P-Pharma, INSERM UMRS_938 research team, SATT Lutech and Sorbonne UniversityDisclosure of Interests:Francis Berenbaum Consultant of: Boehringer, Bone Therapeutics, CellProthera, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, 4P Pharma, 4Moving Biotech, Grant/research support from: TRB Chemedica, Coralie Meurot Employee of: 4P-Pharma, Laure Sudre Employee of: 4P-Pharma, Keren Bismuth Employee of: 4P-Pharma, Revital Rattenbach Shareholder of: 4P-Pharma, Employee of: 4P-Pharma, Patrice Denefle Speakers bureau: 4P-Pharma, Consultant of: 4P-Pharma, Pierre Fabre, Mimetas, Employee of: 4P-Pharma, Celine Martin Employee of: 4P-Pharma, Claire Jacques: None declared
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