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Search Results: 1 - 10 of 28870 matches for " Jean-Pierre Pelletier "
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Skeletal involvement in the pathogenesis and outcomes of rheumatoid arthritis and osteoarthritis
Jean-Pierre Pelletier
Arthritis Research & Therapy , 2012, DOI: 10.1186/ar3571
Abstract: In RA, increased osteoclastic activity is responsible for the development of focal osteopenia/erosion and systemic osteoporosis. The increased osteoclast activity in RA has been demonstrated to be linked to a dysregulation of pathways including cell-cell interactions, cytokines, and the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) system. Recent studies have shown that joint erosion in RA is linked to a decrease in long-term physical function.Under OA conditions, the subchondral bone is the site of numerous dynamic morphological changes. These changes are associated with a number of local abnormal biochemical pathways related to the altered metabolism of osteoblasts and osteoclasts. At the early stages of the disease process, increased bone loss and resorption is observed with subchondral bone associated with local production of catabolic factors including cathepsin K and MMP-13. Moreover, OA osteoblasts present an abnormal phenotype resulting in increased production of growth hormones and catabolic factors. In addition, factors such as osteoprotegerin (OPG) and RANKL have been found to be expressed and modulated over time in human OA subchondral bone. Their synthesis varies from being reduced in early OA to being increased in the late stages of the disease. This finding may explain that in the early stages of OA, bone remodeling favors resorption and in the more advanced stages of the disease, bone formation is predominant.Magnetic resonance imaging (MRI) studies in knee OA patients have shown that the subchondral bone is frequently the site of signal alterations-bone marrow lesions (BML) - indicative of a great variety of morphological changes. BML and cartilage loss have been linked in several studies. Moreover, studies have identified, in OA patients, a number of risk factors for total knee replacement including BMLs.The paradigms regarding the role of bone lesions in arthritic diseases raise a number of important questions. A comprehensive
Reliability and sensitivity to change of IW-TSE versus DESS magnetic resonance imaging sequences in the assessment of bone marrow lesions in knee osteoarthritis patients: Longitudinal data from the Osteoarthritis Initiative (OAI) cohort  [PDF]
Jean-Pierre Raynauld, Lukas Martin Wildi, Fran?ois Abram, Thomas Moser, Jean-Pierre Pelletier, Johanne Martel-Pelletier
Journal of Biomedical Science and Engineering (JBiSE) , 2013, DOI: 10.4236/jbise.2013.63A043
Abstract:

Background: Bone marrow lesions (BMLs) are associated with osteoarthritis (OA). We assessed the performance of two commonly used MRI sequences, IW-TSE and DESS, for reliability in the detection of BMLs and sensitivity to estimate change over time. We suggested that the IW-TSE would demonstrate higher sensitivity to change than DESS in the assessment of BML prevalence and change over time. This study was performed using a subset of the Osteoarthritis Initiative (OAI) cohort. Methods: A sub-group of 144 patients was selected from the OAI progression cohort who all had IW-TSE and DESS MRI acquisitions at baseline and 24 months. BMLs were assessed using a semi-quantitative scale in the global knee, medial and lateral compartments, and subregions. Intra-reader reliability was assessed on a subset of 51 patients. Results: Intra-reader reliability was substantial for the global knee ≥ 0.64, medial ≥ 0.70, and lateral ≥ 0.63 compartments for IW-TSE and DESS. The prevalence of BML detected at baseline was only slightly greater for IW-TSE compared to DESS. The mean BML score at baseline was significantly higher (p ≤ 0.006) for the IW-TSE than the DESS. However, mean change at 24 months was similar for both sequences for all regions except the medial compartment (p = 0.034) and medial femur (p = 0.015) where they were significantly higher for DESS than IW-TSE. Moreover, the prevalence of BML change at 24 months was similar in all regions except the global knee (p = 0.047) and the lateral tibial plateau (p = 0.031). Conclusion: This study does not suggest superior sensitivity to change of one sequence over the other for almost all the regions. The only difference is a higher BML mean change over time detected by the DESS sequence in the medial compartment and femur. These data bring into perspective that both sequences seem equivalent regarding their use for the assessment of BML in clinical trials.

Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow
Jean-Pierre Pelletier, Johanne Martel-Pelletier, Jean-Pierre Raynauld
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar1932
Abstract: Osteoarthritis (OA) is the most common of the musculoskeletal diseases. Within the context of the ageing population, it is rapidly becoming a significant medical and financial burden to the world. Knowledge of its clinical manifestations and effect on quality of life has helped the medical community to appreciate the real impact of the disease on the health of a steadily increasing number of patients. In response to the need for better medical treatments for OA, several therapeutic strategies have been developed. It is expected that new therapies currently in development will prevent the progression of this debilitating disease. Although significant progress has recently been made in the treatment of a number of arthritic diseases, including rheumatoid arthritis (RA), many difficulties encountered in OA research have hindered the development of effective treatments. The disease develops and changes slowly, and clinically represents a heterogeneous group of disorders that are often referred to as osteoarthritic diseases. The absence of objective and definitive biochemical markers has also been a major hurdle for clinical and therapeutic research.The development of disease-modifying osteoarthritis drugs (DMOADs) is a rather complex process. A number of obstacles remain including regulatory issues, length of clinical trials, the lack of validation and consensus on new biological markers, and the fact that recent developments in more effective imaging technology are not yet commonly used. Moreover, the duration of treatment is likely to be life long. Most of the DMOADs that have been brought into development thus far have failed because of their safety profile or lack of efficacy. In this regard, one might wonder whether some negative findings of trials might be accounted for by the lack of suitable technology to assess and quantify disease progression reliably. Fortunately, studies completed and underway are providing information that may soon allow us to overcome thes
The Novartis-ILAR Rheumatology Prize 2001 Osteoarthritis: from molecule to man
Jean-Pierre Pelletier, Johanne Martel-Pelletier
Arthritis Research & Therapy , 2001, DOI: 10.1186/ar378
Abstract: The Novartis-ILAR Rheumatology Prize was awarded at the 20th ILAR Congress of Rheumatology in Edmonton, Canada in August 2001. The Editors-in-Chief would like to inform readers that this Commentary has not undergone peer-review, because it is based upon the acceptance speech for the Prize.In our work on osteoarthritis, we identified several enzymatic pathways that are intimately related to the development of this disease. More specifically, we demonstrated that, although the matrix metalloprotease (MMP) family is of pivotal importance in the degradation of osteoarthritic cartilage [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] (Fig. 1), the serine- and cysteine-dependent proteases [27,28,29,30] also play a significant role. We were among the first to introduce and demonstrate the importance of an imbalance in enzymes and their specific inhibitors (tissue inhibitor of MMP, cathepsin B-inhibitors and plasminogen activator/plasmin/plasminogen activator inhibitor-1) in osteoarthritic tissues. This concept is now well recognized as an intimate element in the pathogenesis of osteoarthritis.In recent years, we have been involved in the discovery of a new collagenase, collagenase-3 (MMP-13), in cartilage and demonstrated its involvement in the osteoarthritis disease process [18]. We were also the first group to clone human collagenase-3 promoter, more specifically its 5' flanking region (GenBank #U52692) [20]. From the work undertaken in our laboratory, we have come to the hypothesis that collagenase-3, in contrast to collagenase-1 (MMP-1), is involved in the remodeling phase of osteoarthritic cartilage [21,22,23,24,26]. Moreover, we also found that, although many cytokines and factors can upregulate collagenase-3, transforming growth factor (TGF)-β appears to be the factor responsible for its upregulation in vivo in osteoarthritic cartilage [21,24,26].Altogether, these findings have proven to be of utmost importance, as some pharmaceutical companies
Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling
Christelle Boileau, Steeve Tat, Jean-Pierre Pelletier, Saranette Cheng, Johanne Martel-Pelletier
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2444
Abstract: The effect of diacerein/rhein on the production of subchondral bone MMP-13 was determined by enzyme-linked immunosorbent assay. Signalling pathways were evaluated on osteoblasts by Western blot. Osteoclast experiments were performed using cells from the pre-osteoclastic murine cell line Raw 264.7. Osteoclast MMP-13 and cathepsin K activities were determined by specific bioassays and differentiation of these cells quantified by tartrate-resistant acid phosphatase staining.Diacerein and rhein reduced, in a dose-dependent manner, the interleukin-1-beta (IL-1β)-induced MMP-13 production in OA subchondral bone. This effect occurred through the inhibition of ERK1/2 (extracellular signal-regulated kinase-1/2) and p38. In osteoclasts, they significantly reduced the activity of MMP-13 and cathepsin K. Moreover, these drugs effectively blocked the IL-1β effect on the osteoclast differentiation process and the survival of mature osteoclasts.Altogether, these data suggest that diacerein/rhein could impact the abnormal subchondral bone metabolism in OA by reducing the synthesis of resorptive factors and osteoclast formation.Osteoarthritis (OA) is considered a complex illness. Although we may not yet completely know all of the initiating factors involved in the degeneration of the articular tissues, significant progress regarding the etiopathogenesis of this disease has been made. For decades, the prevailing concept has centered on the destruction of the articular cartilage. There is now substantial evidence not merely that alterations in the subchondral bone metabolism are secondary manifestations of OA, but that they comprise an integral component of the disease, and data suggest a key role played by the subchondral bone in the initiation and/or progression of articular tissue degeneration.Several reports have indicated that the subchondral bone remodelling that occurs during OA involves both bone resorption and bone formation. Studies allowing chronological evaluation in anima
The shunt from the cyclooxygenase to lipoxygenase pathway in human osteoarthritic subchondral osteoblasts is linked with a variable expression of the 5-lipoxygenase-activating protein
Kelitha Maxis, Aline Delalandre, Johanne Martel-Pelletier, Jean-Pierre Pelletier, Nicolas Duval, Daniel Lajeunesse
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar2092
Abstract: Osteoarthritis (OA) is the leading cause of disability among the elderly population [1]. Despite its prevalence, we still do not fully understand the etiology, pathogenesis and progression of this disease [2,3]. OA progresses slowly and has a multifactorial origin. The disease is characterized by the degradation and loss of articular cartilage, and hypertrophic bone changes with osteophyte formation and subchondral plate thickening [4,5]. It includes changes in articular cartilage and surrounding bone, and an imbalance in loss of cartilage through matrix degradation and an attempt to repair this matrix [4,5]. Specific interactions between bone and cartilage have not been clearly defined in OA; however, there is mounting evidence to indicate a direct intervention of the bone compartment in the initiation and progression of OA [6-8]. We already identified that a growth factor, hepatocyte growth factor, is produced more abundantly by OA osteoblasts than by normal osteoblasts, yet hepatocyte growth factor accumulates in cartilage matrix and is more abundant in OA cartilage [9].As the initiating events leading to OA are still poorly defined, clinical intervention still targets the reduction of pain and discomfort in afflicted patients. Conventional non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases (COX-1 and/or COX-2), the key enzymes that metabolize arachidonic acid into prostaglandins and thromboxanes [10,11]. The decrease in prostaglandin and thromboxane levels is probably the basis for the anti-inflammatory and analgesic activity of the NSAIDs that are widely used for the treatment of OA. Newer drugs (coxibs) have in recent years targeted the selective reduction of COX-2 activity because this inducible form is expressed in response to inflammation, and coxibs are safer for the gastrointestinal tract. However, long-term inhibition of COX-2 could lead to a shunt to the 5-lipoxygenase (5-LO) pathway, as we observed in vitro with OA osteoblasts [12],
Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic and proinflammatory pathways capable of inducing cartilage degradation: a basic science study
Christelle Boileau, Nathalie Amiable, Johanne Martel-Pelletier, Hassan Fahmi, Nicolas Duval, Jean-Pierre Pelletier
Arthritis Research & Therapy , 2007, DOI: 10.1186/ar2329
Abstract: Osteoarthritis (OA) can be defined as a complex degradative and repair process in cartilage, subchondral bone, and synovial membrane. The factors responsible for the appearance and progression of joint structural changes in OA have been the subject of intensive research for a few decades. Although significant progress has been made in the understanding of the pathophysiological pathways responsible for some of the changes, much remains to be done to establish a therapeutic intervention that can effectively reduce or stop the progression of the disease.OA is characterized mainly by degradation of the cartilage. The alterations in OA cartilage are numerous and involve morphologic and synthetic changes in chondrocytes as well as biochemical and structural alterations in the extracellular matrix macromolecules [1]. In OA, the chondrocytes are the first source of enzymes responsible for cartilage matrix catabolism, and it is widely accepted that the metalloproteinase (MMP) family has a major involvement in the disease process [2]. Moreover, considerable evidence has accumulated indicating that the proinflammatory cytokines synthesized and released by chondrocytes and synovial membrane are crucial in OA cartilage catabolic processes and have an important impact in the development/progression of the disease [1].In addition to cytokines, other mediators could play a major role in the OA pathological process. A member of the newly identified cell membrane receptor family, the proteinase-activated receptors (PARs), has been shown to be involved in inflammatory pathways. These receptors belong to a novel family of seven-transmembrane G protein-coupled receptors that are activated through a unique process. The cleavage by serine proteases of the PAR N-terminal domains unmasks a new N-terminal sequence that acts as a tethered ligand, binding and activating the receptor itself [3,4]. This activation is an irreversible phenomenon: the cleaved receptor is activated, internalized, a
Regulation of the IGFBP-5 and MMP-13 genes by the microRNAs miR-140 and miR-27a in human osteoarthritic chondrocytes
Ginette Tardif, David Hum, Jean-Pierre Pelletier, Nicolas Duval, Johanne Martel-Pelletier
BMC Musculoskeletal Disorders , 2009, DOI: 10.1186/1471-2474-10-148
Abstract: Gene expression was determined by real-time PCR. The effect of each miRNA on IGFBP-5 and MMP-13 expression/production was evaluated by transiently transfecting their precursors (pre-miRNAs) and inhibitors (anti-miRNAs) into human OA chondrocytes. Modulation of IGFBP-5, miR-140 and miR-27a expression was determined upon treatment of OA chondrocytes with cytokines and growth factors.IGFBP-5 was expressed in human chondrocytes with its level significantly lower (p < 0.04) in OA. Five computational algorithms identified miR-140 and miR-27a as possible regulators of MMP-13 and IGFBP-5 expression. Data showed that both miRNAs were expressed in chondrocytes. There was a significant reduction (77%, p < 0.01) in miR-140 expression in OA compared to the normal chondrocytes, whereas miR-27a expression was only slightly decreased (23%). Transfection with pre-miR-140 significantly decreased (p = 0.0002) and with anti-miR-140 significantly increased (p = 0.05) IGFBP-5 expression at 24 hours, while pre-miR-27a did not affect either MMP-13 or IGFBP-5. Treatment with anti-miR-27a, but not with anti-miR-140, significantly increased the expression of both MMP-13 (p < 0.05) and IGFBP-5 (p < 0.01) after 72 hours of incubation. MMP-13 and IGFBP-5 protein production followed the same pattern as their expression profile. These data suggest that IGFBP-5 is a direct target of miR-140, whereas miR-27a down-regulates, likely indirectly, both MMP-13 and IGFBP-5.This study is the first to show the regulation of these miRNAs in human OA chondrocytes. Their effect on two genes involved in OA pathophysiology adds another level of complexity to gene regulation, which could open up novel avenues in OA therapeutic strategies.Many factors contribute to the overall degradation of cartilage observed in osteoarthritis (OA), either directly or indirectly by modulating anabolic factors. Examples of such molecules are the matrix metalloprotease (MMP)-13 and the insulin-like growth factor binding protein (IGF
Fully automated system for the quantification of human osteoarthritic knee joint effusion volume using magnetic resonance imaging
Wei Li, Fran?ois Abram, Jean-Pierre Pelletier, Jean-Pierre Raynauld, Marc Dorais, Marc-André d'Anjou, Johanne Martel-Pelletier
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar3133
Abstract: MRI examinations consisted of two axial sequences: a T2-weighted true fast imaging with steady-state precession and a T1-weighted gradient echo. An automated joint effusion volume quantification system using MRI was developed and validated (a) with calibrated phantoms (cylinder and sphere) and effusion from knee OA patients; (b) with assessment by manual quantification; and (c) by direct aspiration. Twenty-five knee OA patients with joint effusion were included in the study.The automated joint effusion volume quantification was developed as a four stage sequencing process: bone segmentation, filtering of unrelated structures, segmentation of joint effusion, and subvoxel volume calculation. Validation experiments revealed excellent coefficients of variation with the calibrated cylinder (1.4%) and sphere (0.8%) phantoms. Comparison of the OA knee joint effusion volume assessed by the developed automated system and by manual quantification was also excellent (r = 0.98; P < 0.0001), as was the comparison with direct aspiration (r = 0.88; P = 0.0008).The newly developed fully automated MRI-based system provided precise quantification of OA knee joint effusion volume with excellent correlation with data from phantoms, a manual system, and joint aspiration. Such an automated system will be instrumental in improving the reproducibility/reliability of the evaluation of this marker in clinical application.Joint effusion is frequently associated with articular disorders. In osteoarthritis (OA), the effusion is an important marker of the disease flare-up, and its quantification could be helpful as a treatment outcome measure. The most common means used to quantify joint effusion volume is arthrocentesis. A major drawback of this method, however, in addition to being invasive and somewhat painful, is that it often fails to estimate the total joint effusion volume accurately [1]. Several methods for the calculation of the "true" joint effusion volume have been described, and thes
Analysis of the precision and sensitivity to change of different approaches to assess cartilage loss by quantitative MRI in a longitudinal multicentre clinical trial in patients with knee osteoarthritis
Jean-Pierre Raynauld, Johanne Martel-Pelletier, Fran?ois Abram, Marc Dorais, Boulos Haraoui, Denis Choquette, Peter Bias, Karl H Emmert, Stefan Laufer, Jean-Pierre Pelletier
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2543
Abstract: Three hundred and fifty-five patients with symptomatic knee OA were recruited for a two-year, double-blind, randomised clinical trial evaluating the effect of 200 mg licofelone twice daily and 500 mg naproxen twice daily on cartilage loss, and 301 patients had baseline MRI. MRIs were performed at baseline, 6, 12 and 24 months. Cartilage volume and thickness in the global joint, medial and lateral compartments, and central weight-bearing subregions of the medial and lateral femoral condyles and tibial plateaus were analysed. Data were analysed for the mean value imputed for intent-to-treat (ITT-MVI) and statistical analyses were performed using two-sample Student's t-test.Cartilage mean thickness loss in the global joint, lateral and medial compartments, as well as in medial compartments stratified according to patients with or without meniscal extrusion, was significantly less in the licofelone compared with the naproxen group at 12 and 24 months. Interestingly, these data were similar to those found when using cartilage volume loss as an outcome. Although greater cartilage volume and mean thickness loss was seen in central weight-bearing subregions of the medial and lateral compartments compared with the whole compartment and also in patients with meniscal lesions/extrusion, suggesting good sensitivity to change, its high standard deviation precluded for the condyles a high statistical power and abrogated statistically significant differences between the treatment groups.These data demonstrate that both the measurement of cartilage thickness and that of cartilage volume provide the same level of sensitivity to estimate cartilage loss in a clinical trial. However, the potential of gaining statistical power with the use of thickness/volume change in knee subregions as an outcome seems negated by high inter-patient variability. Moreover, there is no superiority in statistical power by selecting patients with meniscal extrusion.Osteoarthritis (OA) is characterised by a
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