http://hdl.handle.net/2268/117 Search this channel search http://orbi.ulg.ac.be/simple-search http://hdl.handle.net/2268/148448 Title: How to define responders in osteoarthritis <br/> <br/>Author, co-author: Cooper, Cyrus; Adachi, Jonathan D; Bardin, Thomas; Berenbaum, Francis; Flamion, Bruno; Jonsson, Helgi; Kanis, John A; Pelousse, Franz; Lems, Willem F; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne; Reiter, Susanne; Reginster, Jean-Yves; Rizzoli, René; Bruyère, Olivier <br/> <br/>Abstract: Background: Osteoarthritis is a clinical syndrome of failure of the joint accompanied by varying degrees of joint pain, functional limitation, and reduced quality of life due to deterioration of articular cartilage and involvement of other joint structures. Scope: Regulatory agencies require relevant clinical benefit on symptoms and structure modification for registration of a new therapy as a disease-modifying osteoarthritis drug (DMOAD). An international Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and International Osteoporosis Foundation was convened to explore the current burden of osteoarthritis, review current regulatory guidelines for the conduct of clinical trials, and examine the concept of responder analyses for improving drug evaluation in osteoarthritis. Findings: The ESCEO considers that the major challenges in DMOAD development are the absence of a precise definition of the disease, particularly in the early stages, and the lack of consensus on how to detect structural changes and link them to clinically meaningful endpoints. Responder criteria should help identify progression of disease and be clinically meaningful. The ideal criterion should be sensitive to change over time and should predict disease progression and outcomes such as joint replacement. Conclusion: The ESCEO considers that, for knee osteoarthritis, clinical trial data indicate that radiographic joint space narrowing40.5mm over 2 or 3 years might be a reliable surrogate measure for total joint replacement. On-going research using techniques such as magnetic resonance imaging and biochemical markers may allow the identification of these patients earlier in the disease process http://hdl.handle.net/2268/147943 Title: Investigation of potential new targets for the diagnosis and/or the treatment of osteoarthritis <br/> <br/>Author, co-author: Lambert, Cécile; Dubuc, J.-E.; Montell, E.; Vergés, J.; Munaut, Carine; Noël, Agnès; Henrotin, Yves <br/> <br/>Abstract: Purpose: Synovial inflammation plays a key role in the pathophysiology process of osteoarthritis (OA). We have previously compared the gene expression pattern of synovial cells isolated from inflammatory (I) or normal/reactive (N/R) areas of a synovial membrane harvested from the same OA patient. We identified a large number of mediators belonging to key pathways involved in OA pathogenesis. The aim of this study was to validate different potential new targets for the diagnosis and/or the treatment OA. Methods: Synovial cells (SC) were isolated from synovial specimens obtained from OA patients undergoing knee replacement. The inflammatory status of the synovial membrane was characterized according to macroscopic criteria. The biopsies from N/R and I areas were cultured separately for a period of 7 days. Microarray gene expression profiling between N/R and I areas was performed. The biological relevance of up- and down-regulated genes was analyzed with Ingenuity Pathways Analysis. Western blot and immunohistochemistry confirmed the identified genes most differentially expressed in the key pathways. The production of the triggering receptor expressed on myeloid cells-1 (TREM1), the alarmin S100 calcium binding protein A9 (S100A9), the wingless-type MMTV integration site family, member 5A (Wnt-5A) and the stanniocalcin 1 (STC1) were evaluated by Western blot. S100A9, hyaluronan synthase-1 (HAS1) and STC1 expression and localization were investigated by immunohistochemistry. Results: 896 genes differentially expressed in N/R and I areas were identified. The key pathways were related to inflammation, cartilage metabolism, Wnt signaling and angiogenesis. In the inflammatory gene pattern, TREM1 and S100A9 were strongly upregulated. We validated the production of these proteins in OA synovial biopsies by Western blot. TREM1 and S100A9 were increased in I compared to N/R synovial cells culture. S100A9 was observed in the perivascular area and in sublining cells in I synovial biopsies, but not in N/R biopsies. An increased staining was also observed in the intima lining layer of I when compared to N/R biopsies. The most upregulated anabolism enzyme in I synovial biopsies was HAS1. Using immunohistochemistry, we observed in I areas an increase of the HAS1-positive cells mainly in the intima lining. We also studied the protein production of Wnt-5A, the most upregulated intermediate of Wnt signaling pathway. The protein level was increased in I compared to N/R areas. Finally, in the angiogenesis pathway, one the most u-regulated gene was STC1. A significant increase of STC1 production was observed in I areas compared to N/R areas by Western blot. This result was also supported by the immunohistochemical analysis. In I area, the staining for STC1 was more intense in perivascular and sublining cells. Conclusions: Synovial membrane inflammation is a key target for OA treatments. In this work, we have identified proteins involved in the synovitis pathways like angiogenesis, cells infiltration and matrix remodeling. These proteins could be targeted by drugs and used as companion biomarkers for evaluating their efficacy. Although qualitative, our results could also yield to the identification of markers of the disease. This investigation has to be further pursued. http://hdl.handle.net/2268/147941 Title: Effects of chondroitin sulfate on the gene expression profile in the inflamed synovial membrane <br/> <br/>Author, co-author: Lambert, Cécile; Dubuc, J-E; Montell, E.; Vergés, J.; Henrotin, Yves <br/> <br/>Abstract: Purpose: The aim of the present work was to identify the differentially expressed genes between the inflammatory (I) and normal/reactive (N/R) synovial areas using a unique ex vivo culture model. In a second step, we investigated the genetic modulatory effects of chondroitin sulfate (CS) in this model. Methods: Synovial cells (SC) were isolated from OA synovial specimens obtained from 12 patients undergoing knee replacement. The inflammatory status of the synovial membrane was characterized according to macroscopic criteria. At the surgery time, the synovial membrane was dissected and biopsies from N/R and I areas cultured separately for a period of 7 days in the absence or in the presence of highly purified bovine CS (200 µg/ml, Bioibérica S.A., Barcelona, Spain). Total RNA was extracted using the RNeasy Mini Kit. RNA purity and quality were evaluated using the Experion RNA StdSens Analysis kit (Bio-rad Laboratories). Gene expression profiling was performed using Illumina’s multi-sample format Human HT-12 BeadChip (Illumina Inc.). Differential analysis was performed with the BRB array tools software. Class Comparison test between N/R and I conditions, N/R and N/R-CS conditions and I and I-CS conditions was based on paired t-test where N/R and I, N/R and N/R-CS and I and I-CS were paired for each patient. The biological relevance of up- and down-regulated genes was analyses with Ingenuity Pathways Analysis (Ingenuity® Systems). Results: From among 47000 probes, 18253 were filtered out. Probes with a p-value below than 0.005 were chosen and classified as up- or down-regulated ones. By this way, 465 differentially expressed genes between N/R and I areas were identified. Many inflammatory mediators appear differentially expressed. The interferon alpha-inductible protein 6 (IFI6) was the most up-regulated. We also identified the hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1), the cathepsin K (CTSK), the chemokine (C-X-C motif) ligand 1 (CXCL1) and the EBV-induced G-protein coupled receptor 2 (EBI2). The differential expression of intermediates involved in angiogenesis pathway was also revealed between N/R and I areas. Among them, R-spondin-3 (RSPO3), the secreted phopshoprotein 1 (SPP1) and aquaporin 9 (AQP9) were up-regulated whereas ADAMTS1 was down-regulated. Finally, in the Wnt signaling, RSPO3 was up-regulated unlike dickkopf homolog 3 (DKK3) which was in turn down-regulated. We next performed a class comparison test between N/R and N/R-CS in one hand and between I and I-CS the other hand. 489 genes were identified as differentially expressed genes between N/R and N/R-CS conditions while 219 genes were identified between I and I-CS conditions. In this latter, our attention was focused on the down-regulated genes. Among them, we identified a number implicated in angiogenesis and cell migration pathways. Thus, the endothelial cell-specific molecule-1 (ESM1), the Transmembrane-4-L-six-family-1 (TM4SF1), the 5’-Ectonucleotidase (NT5E) and the growth arrest-specific gene 6 (GAS6) were down-regulated by CS. Conclusions: Our work demonstrates the differential gene expression profile between paired non inflammatory and normal/reactive areas of synovial membrane as well as the modulatory effects of CS on gene expression in the inflammatory areas, especially regarding genes involved in both angiogenesis and cell migration. http://hdl.handle.net/2268/147940 Title: Effects of chondroitin sulfate on the gene expression profile in IL-1β stimulated synovial fibroblast cells cultures <br/> <br/>Author, co-author: Lambert, Cécile; Dubuc, Jean-Emile; Montell, E.; Vergés, J.; Henrotin, Yves <br/> <br/>Abstract: Purpose: Chondroitin sulfate (CS) is one the most used molecules in the management of OA. In this study, we performed a microarray analysis and identified a differential expression profile between control and IL-1β stimulated synovial fibroblast cells cultures. In a second step, we investigated the effects of CS on this gene expression profile. Methods: OA synovial specimens were obtained from 12 patients undergoing knee replacement. At the surgery time, the synovial membrane was dissected. Synovial fibroblast cells (SFC) were enzymatically isolated and used after four passages (P4). SFC were pre-treated 1 hour with highly purified bovine CS (200 µg/ml, Bioibérica S.A., Barcelona, Spain) before treatment with IL-1β (1 ng/ml) for 24 hours. Total RNA was extracted using the RNeasy Mini Kit. RNA purity and quality were evaluated using the Experion RNA StdSens Analysis kit (Bio-rad Laboratories). Gene expression profiling was performed using Illumina’s multi-sample format Human HT-12 BeadChip (Illumina Inc.). Differential analysis was performed with the BRB array tools software. Class comparison test between control (Ctl) and interleukin (IL)-1β conditions, Ctl and Ctl/CS and IL-1β and IL-1β/CS conditions was based on paired t-test where Ctl and IL-1β, Ctl and Ctl/CS and IL-1β and IL-1β/CS were paired for each patient. The biological relevance of up- and down-regulated genes was analyses with Ingenuity Pathways Analysis (Ingenuity® Systems). Probes with a p-value below 0.001 were chosen and classified as up- or down-regulated ones. Results: 3308 genes were identified as differentially expressed genes between Ctl and IL-1β conditions. We observed a differential profile of expression of major pathways involved in OA pathogenesis. The key identified pathways were related to inflammation, complement cascade, angiogenesis, cartilage catabolism and anabolism and Wnt signaling. In the inflammatory network, the most upregulated cytokines were IL-8 and IL-6 with a fold change of 156.25 and 58.8 respectively. We also identified several chemokines, enzymes and metallothioneins (MTs). Complement factor B (CFB) and complement component 3 (C3) are two factors upregulated in the inflammatory complement cascade. We also identified some genes implicated in the angiogenesis pathway. The most upregulated was Stanniocalcin 1 (STC1) with a fold change of 9.09. The differential expression of intermediates involved in both cartilage anabolism and catabolism was revealed by the IL-1β stimulation, showing an imbalance in favour of catabolism. MMP-3 was largely upregulated (fold change of 62.5). Wnt 5A and low density lipoprotein receptor-related protein (LRP8) were significantly upregulated while frizzled homolog 2 (FZD2) and dickkopf homolog 3 (DKK3) were downregulated in the Wnt signaling pathway. We next performed a class comparison test between Ctl and Ctl/CS in one hand and IL-1β and IL-1β/CS on the other hand. 660 genes were identified as differentially expressed between Ctl and Ctl/CS conditions while 241 genes were identified between IL-1β and IL-1β/CS. Among them, our attention was focused on two genes upregulated in the presence of CS: lysyl oxidase-like 4 (LOXL4) and claudin 11 (CDLN11), two genes that negatively regulate cell invasion. Conclusions: We here evidenced in synovial fibroblast cells the modulation of gene expression following IL-1β stimulation. We also demonstrated the modulatory effects of CS on gene expression and isolated several CS-modulated genes of interest such as LOXL4 and CDLN11, which could constitute new mechanisms of action of the molecule and contribute to explain the symptomatic efficacy of CS in the treatment of OA. http://hdl.handle.net/2268/147939 Title: OARSI recommended performance-based tests to assess physical function in people with established hip and knee osteoarthritis <br/> <br/>Author, co-author: Dobson, F.; Hinman, R.S.; Roos, E.M.; Abbott, J.H.; Stratford, P.; Davis, A.; Buchbinder, R.; Snyder-Mackler, L.; Henrotin, Yves; Thumboo, J.; Bennell, K.L. http://hdl.handle.net/2268/147932 Title: The intra-articular injection of a new chitosan biomaterial prevents the progression of osteoarthritis in ACLT rabbit model <br/> <br/>Author, co-author: Oprenyeszk, Frédéric; Chausson, Mickael; Maquet, Véronique; Dubuc, Jean-Emile; Henrotin, Yves <br/> <br/>Abstract: Purpose To evaluate the effects of a single intra-articular injection of a new biomaterial consisting in a mix of alginate-chitosan (AC) beads and a viscous thermogelling chitosan-based (H) hydrogel on cartilage lesion in osteoarthritis (OA) rabbit model. These effects were compared to those obtained with the intra-articular injection of either chitosan-based (H) hydrogel without the AC bead or saline solution. Methods OA was surgically induced by the transection of the anterior cruciate ligament (ACLT) in HYLA albino rabbits. One week after surgery, animals were randomly divided into 3 groups: group I (n=7): mix of AC beads and H hydrogel; group II (n=7): H hydrogel alone; group III (n=7): saline solution (control). The treatments (900 µl) were injected intra-articularly. X-rays from the right knee were performed before surgery, at the time of injection and at sacrifice. The standard radiographs were acquired in extension and scored by the Kellgren and Lawrence (K&L) scale. After 6 weeks, animals were euthanized and the right joint was dissected. The macroscopic evaluation of cartilage from femoral condyles and tibial plateaus stained with India ink was done. Histological sections stained with Safranine-O/fast green from bearing areas of each compartment were evaluated according to the OARSI histological score. Briefly, the evaluation considered: staining of the cartilage matrix (0-6), cartilage structure (0-11), chondrocyte density (0-4) and cluster formation (0-3), where 0 represented a normal situation and 24 points the maximum severity score. Blood samples were collected the day of injection and prior the sacrifice. Prostaglandin E2 (PGE2) and C-reactive protein (CRP) were measured in serum using immunoassays. Results The X-rays analysis showed a significant decrease (p <0.05) of the K&L score in group I (AC beads and H hydrogel; 1.5 ± 0.2) compared with group II (H hydrogel; 2.2 ± 0.5) and group III (saline solution; 3.0 ± 0.4). The size and the severity of the macroscopic OA cartilage lesion tended to decrease in group I compared to the other groups. The histological global score that refers to all compartments of the knee joint was significantly decreased in group I (11.0 ± 0.7) compared to group II (14.4 ± 0.6, p <0.01) and group III (14.8 ± 0.6, p <0.001). No significant variation of PGE2 and CRP serum levels were observed in each after 6 weeks follow-up whatever the treatment injected. Conclusions This study showed that a biphasic hydrogel composed by AC beads and H hydrogel prevented OA in rabbit with ACL transection. This effect was not observed with the hydrogel alone, suggesting that AC beads play a role in joint protection. The preventive effect was observed in all joint compartments indicating a global protective effect of this new viscosupplementation. http://hdl.handle.net/2268/147562 Title: Equivalence of a single dose (1200mg) compared to a 3-time a day dose (400mg) of chondroitin 4&6 sulfate in patients with knee osteoarthritis: Results of a randomized double blind placebo controlled study <br/> <br/>Author, co-author: Zegels, Brigitte; LEONORI, Lorenzo; Crozes, P; Uebelhart, D; Bruyère, Olivier; Reginster, Jean-Yves http://hdl.handle.net/2268/147554 Title: Reproducibility of joint space width assessment when external calibration on the radiograph is missing <br/> <br/>Author, co-author: DEROISY, Rita; Reginster, Jean-Yves; Bruyère, Olivier http://hdl.handle.net/2268/147553 Title: Validity of the French hip and knee replacement expectations surveys <br/> <br/>Author, co-author: NEUPREZ, Audrey; François, Garance; Delcour, JP; Fatemi, F; Bruyère, Olivier; Gosset, Christiane; Mancuso, C; Gillet, Philippe; Reginster, Jean-Yves http://hdl.handle.net/2268/147550 Title: Evaluation of the impact of a 6-month training by whole body vibration on the risk of falls among nursing home residents <br/> <br/>Author, co-author: Beaudart, Charlotte; Buckinx, Fanny; Demonceau, Marie; Maquet, Didier; Crielaard, Jean-Michel; Reginster, Jean-Yves; Bruyère, Olivier http://hdl.handle.net/2268/147547 Title: Clinical characteristics of patients responsive to whole body vibration <br/> <br/>Author, co-author: Beaudart, Charlotte; Buckinx, Fanny; Maquet, Didier; Crielaard, Jean-Michel; Reginster, Jean-Yves; Bruyère, Olivier http://hdl.handle.net/2268/147540 Title: Quantitative gait assessment using an accelerometer technology as a predictive tool of falls among nursing home residents: a 6-month prospective study <br/> <br/>Author, co-author: Bruyère, Olivier; Detalle, Anne-Sophie; Demonceau, Marie; Beaudart, Charlotte; Croisier, Jean-Louis; Crielaard, Jean-Michel; Reginster, Jean-Yves; Maquet, Didier http://hdl.handle.net/2268/147537 Title: Changes in the structure and the symptoms of the osteoarthritis knee and prediction of future knee replacement over an 8-year follow-up period <br/> <br/>Author, co-author: Bruyère, Olivier; Cooper, Cyrus; Pavelka, Karel; Rabenda, Véronique; Buckinx, Fanny; Beaudart, Charlotte; Reginster, Jean-Yves http://hdl.handle.net/2268/147534 Title: Cost-effectiveness of vitamin D and calcium supplementation in the treatment of postmenopausal women <br/> <br/>Author, co-author: Hiligsmann, Mickaël; Ben Sedrine, Wafa; Rabenda, Véronique; Bruyère, Olivier; Reginster, Jean-Yves http://hdl.handle.net/2268/147529 Title: What is the predictive value of MRI for the occurrence of hard clinical endpoints in knee osteoarthritis? <br/> <br/>Author, co-author: Pelletier, Jean-Pierre; Peterfy, Charles; Brandi, Maria Luisa; Bruyère, Olivier; Chapurlat, Roland; Cicuttini, Flavia; Conaghan, P; Doherty, M; Genant, Harry K; Guermazi, A; Hochberg, Mark; Hunter, D; Kanis, John A; Kloppenburg, Margreet; Laredo, JD; Martel-Pelletier, Johanne; McAlindon, T; Nevitt, M; Raynauld, Jean-Pierre; Rizzoli, René; Zilkens, C; Reginster, Jean-Yves; Cooper, Cyrus http://hdl.handle.net/2268/147527 Title: Role of nutraceuticals in the symptomatic and structural management of osteoarthritis <br/> <br/>Author, co-author: Bruyère, Olivier http://hdl.handle.net/2268/147526 Title: Health economics in osteoarthritis <br/> <br/>Author, co-author: Hiligsmann, Mickaël; Cooper, Cyrus; Arden, Nigel; Boers, Marteen; Branco, Jaime; Brandi, Maria Luisa; Bruyère, Olivier; Guillemin, Francis; Hochberg, Marc; Hunter, David; Kanis, John A; Kvien, Tore; Laslop, Andrea; Petit-Dop, Florence; Pelletier, Jean-Pierre; Pinto, Daniel; Reiter, Susanne; Rizzoli, René; Rovati, Lucio C; Severens, Hans; Silverman, Stuart; Tsouderos, Yannis; Tugwell, Peter; Reginster, Jean-Yves http://hdl.handle.net/2268/147522 Title: What is the value of biomarkers for drug development in osteoarthritis? <br/> <br/>Author, co-author: Lotz, Martin; Martel-Pelletier, Johanne; Christiansen, Claus; Berenbaum, Francis; Brandi, Maria Luisa; Bruyère, Olivier; Chapurlat, Roland; COLLETTE, Julien; Cooper, Cyrus; Heinegard, Dick; Kanis, John A; Kraus, V; Laslop, Andrea; Lems, Willem; Lohmander, S; Meulenbelt, I; Pelletier, Jean-Pierre; Raynauld, Jean-Pierre; Reiter, Susan; Rizzoli, René; Sandel, L; Spector, Tim; Van Spil, Willem E; Reginster, Jean-Yves http://hdl.handle.net/2268/147521 Title: Quality of life in sarcopenia and frailty <br/> <br/>Author, co-author: Rizzoli, René; Reginster, Jean-Yves; Arnal, Jean-François; Bautmans, Ivan; Bischoff-Ferrari, Heike; Biver, Emmanuel; Boonen, Steven; Brandi, Maria Luisa; Chines, Arkadi; Cooper, Cyrus; Dahlin-Ivanoff, Synneve; Epstein, Sol; Kanis, John A; Fielding, Roger A; Goodpaster, Bret; Laslop, Andrea; Malafarina, Vincenzo; Rodriguez Mañas, Leocadio; Mitlak, Bruce; Oreffo, Richard O; Petermans, Jean; Reid, Kieran; Roland, Yves; Sayer, Avan Aihie; Tsouderos, Yannis; Visser, Marjolein; Bruyère, Olivier http://hdl.handle.net/2268/147520 Title: Nonpharmacological management <br/> <br/>Author, co-author: Bruyère, Olivier