Johanne Martel-Pelletier

Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage.

Cartilage specimens from tibial plateaus, obtained from 13 osteoarthritic (OA) patients and seven controls, were selected from three regions: zone A, center of fibrillated area; zone B, area adjacent to fibrillation, and zone C, remote region of plateau. Acid and neutral metalloproteinases and tissue inhibitor of metalloproteinase (TIMP) were extracted with 2 M guanidine. Methods were developed to selectively destroy either proteinases or TIMP to prevent cross-reaction during assay. Acid and neutral proteinases were elevated approximately 150% in OA; TIMP was elevated approximately 50%. A positive correlation (r = 0.50) was found between acid and neutral proteinase activities in OA, but not in controls. Both proteinases were elevated two-to threefold in zones A, B, and C. However, the self-active form of the acid metalloproteinase was elevated only in zones A and B (200%); it correlated well with the Mankin scores, whereas the total activities did not. TIMP was elevated (50%) only in zones A and B. Both the proteinase levels and the Mankin score were elevated to a greater extent in the medial, than in the lateral, compartment. Titration of TIMP against the two metalloproteinases indicates that there is a small excess of inhibitor over enzymes in normal cartilage. In OA, TIMP does not increase to the same extent as the proteinases; the resultant excess of proteinases over TIMP may contribute to cartilage breakdown.

Computer-aided method for quantification of cartilage thickness and volume changes using MRI: validation study using a synthetic model

The primary objective of this study was to develop a computer-aided method for the quantification of three-dimensional (3-D) cartilage changes over time in knees with osteoarthritis (OA). We introduced a local coordinate system (LCS) for the femoral and tibial cartilage boundaries that provides a standardized representation of cartilage geometry, thickness, and volume. The LCS can be registered in different data sets from the same patient so that results can be directly compared. Cartilage boundaries are segmented from 3-D magnetic resonance (MR) slices with a semi-automated method and transformed into offset-maps , defined by the LCS. Volumes and thickness are computed from these offset-maps. Further anatomical labeling allows focal volumes to be evaluated in predefined subregions. The accuracy of the automated behavior of the method was assessed, without any human intervention, using realistic, synthetic 3-D MR images of a human knee. The error in thickness evaluation is lower than 0.12 mm for the tibia and femur. Cartilage volumes in anatomical subregions show a coefficient of variation ranging from 0.11% to 0.32%. This method improves noninvasive 3-D analysis of cartilage thickness and volume and is well suited for in vivo follow-up clinical studies of OA knees.

Metalloproteases and Their Modulation as Treatment in Osteoarthritis

Osteoarthritis (OA) is a disease characterized by a degeneration of articular cartilage. Although the etiology of OA is not yet known and is likely multifactorial, this disease process involves a disturbance in the normal balance of degradation and repair in articular cartilage (1). The breakdown of the cartilage matrix leads to the development of fibrillation, fissures, the appearance of gross ulcerations, and the disappearance of the full thickness surface of the joint. This is accompanied by hypertrophic bone changes with osteophyte formation and subchondral plate thickening. The cartilage matrix breakdown products released into the synovial fluid are phagocytosed by the synovial membrane. Consequently, the membrane becomes hypertrophic and hyperplastic, and an inflammatory reaction is often observed. Although the remodeling of subchondral bone is associated with OA pathology, it is still under debate whether this tissue change initiates or is involved in the progression of cartilage loss.

Use of Quantitative Magnetic Resonance Imaging in the Cross-Sectional and Longitudinal Evaluation of Structural Changes in Knee Osteoarthritis Patients

Assessment of structural damage of the articular cartilage is important for monitoring the progression of osteoarthritis (OA) and evaluating therapeutic response. For many years, clinical studies of drug interventions on symptomatic knee OA have focused mainly on clinical parameters, such as pain and joint function, using self-administered questionnaires but without assessing the effect of treatment on structural changes caused by the disease and the role of treatment in preventing cartilage degradation. Recently, such attempts were made to evaluate cartilage damage and its progression in OA. Serial radiographs of affected joints have appeared as a logical means of documenting the progression of OA over time, providing that a validated, reliable, and easily reproducible technique is used [1]. Improvements in the standardization and interpretation of radiographs have enhanced the reliability of the measurement of the joint space width (JSW) and the evaluation of the joint space narrowing (JSN) [2, 3]. However, the sensitivity to change of this measurement is such that a minimum follow-up of 2 to 3 years and more and large numbers of patients (at least 1500 for a two-arm study) is necessary to establish an effect of pharmacological interventions on OA progression. Moreover, measurement of JSW does not capture information on the cartilage changes alone but is also dependent on the integrity of surrounding tissues, especially the meniscus and the subchondral bone. For instance, enucleation of the knee medial meniscus, which may occur during longitudinal studies, can dramatically change the JSW and affect the reliability of such measurement [4], potentially impairing its use in the assessment of cartilage degradation over time. Finally, the JSW progression provides only one measurement

Modulation of the Expression of Glucocorticoid Receptors in Synovial Fibroblasts and Chondrocytes by Prostaglandins and NSAIDs.

Endogenous glucocorticoids are of prime importance in the maintenance of cellular homeostasis through their binding to specific cell receptors. Under normal conditions, physiological concentrations of cortisol are potentially capable of suppressing metalloprotease synthesis by chondrocytes and synoviocytes. This hormone action is likely to represent one of the major pathways through which the catabolism of cartilage under physiological conditions is kept in a homeostatic state. In osteoarthritis (OA), a severe reduction (about 50%) in the glucocorticoid receptor (GR) level in chondrocytes was found to be sufficient to alter the cellular steroid resistance in terms of the synthesis of destructive enzymes. Prostaglandins of the E series and dibutyryl cyclic AMP increased the GR level in normal and OA human articular chondrocytes. Synthetic PGE1 (misoprostol) also induced upregulation of GR expression in chondrocytes. Naproxen and indomethacin, but not tiaprofenic acid, at therapeutic concentrations, significantly reduced the level of GR in synovial cells. This effect could be reversed by the addition of misoprostol. These findings bring insight into the differential effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the GR system and may provide an explanation for the reduced level of GR found in OA chondrocytes. The addition of synthetic prostaglandins may prove to be of therapeutic importance in the treatment of arthritic diseases by potentiating the effects of therapeutically administered glucocorticoid on the reduction of the catabolism of articular cartilage.

Recent Developments in the Therapy of Osteoarthritis

The last decade has been the scene of several interesting advances in the treatment of osteoarthritis (OA) . Improved understanding regarding the pathophysiology of OA has contributed to the development of new strategies for treatments aimed at specifically and effectively retarding or stopping the progression of this disease.

New Therapeutic Targets for Osteoarthritis

As the most common form of joint disease, osteoarthritis (OA) represents a major cause of morbidity and disability, particularly in the second half of life, as well as a significant burden on health-care resources. Although important advances in understanding the pathophysiologic processes of OA have been made, today’s treatment of the disease still focuses mainly on improving its symptoms (1). As the relationship between the etiology and pathology of OA have become more clearly defined, new concepts and molecular targets for the treatment of this arthritic condition have emerged and have permitted the development of new therapeutic agents. These agents are likely to provide significant progress toward modifying the progression of the structural changes of this disease. The pharmacological agents of this class are named disease-modifying anti-osteoarthritis drugs, or DMOAD, introducing the concept that some drugs may slow the rate of cartilage degeneration, and/or enhance the rate of cartilage repair. The discovery of new agents that have the potential to reduce or stop the progression of the structural changes observed in this disease in humans is most promising and likely to change the therapeutic approach in the near future.

New Therapeutic Targets for Osteoarthritis: The Rewards of Research

As the most common form of joint disease, osteoarthritis (OA) represents a major cause of morbidity and disability, particularly in the second half of life, as well as a significant burden on health-care resources. Although important advances in understanding the pathophysiologic processes of OA have been made, todays treatment of the disease still focuses mainly on improving its symptoms (1). As the relationship between the etiology and pathology of OA have become more clearly defined, new concepts and molecular targets for the treatment of this arthritic condition have emerged and have permitted the development of new therapeutic agents. These agents are likely to provide significant progress toward modifying the progression of the structural changes of this disease. The pharmacological agents of this class are named disease-modifying anti-osteoarthritis drugs, or DMOAD, introducing the concept that some drugs may slow the rate of cartilage degeneration, and/or enhance the rate of cartilage repair. The discovery of new agents that have the potential to reduce or stop the progression of the structural