Changes In Cartilage Structure Research Articles

Current concepts in pediatric musculoskeletal imaging: magnetic resonance imaging

Purpose of review The cartilaginous structures at the ends of growing bones of the immature skeleton are best seen with magnetic resonance imaging. Technologic advances in pediatric musculoskeletal magnetic resonance imaging have led to the development of advances in coil design with improved spatial resolution of both large and small joints. New sequences and higher field strengths now provide new insights into articular cartilage abnormalities. Recent findings The imaging of articular abnormalities in children includes those that affect the synovium, epiphyseal cartilage, and growth plate. Magnetic resonance imaging provides important information in the diagnosis of pediatric musculoskeletal trauma and the management of growth disturbances. Magnetic resonance imaging is now evolving as a tool to manage and monitor injuries that result in juvenile osteochondritis dissecans. Magnetic resonance classification of osteochondral injuries is helping to guide therapy with respect to nonsurgical management of juvenile osteochondritis dissecans. New magnetic resonance sequences are increasing our understanding of the structural changes of cartilage and could be used to monitor children with juvenile rheumatoid arthritis. Summary Understanding the technologic advances in pediatric musculoskeletal magnetic resonance imaging will make it easier to identify the cartilaginous structures of the immature skeleton and common abnormalities. New magnetic resonance imaging techniques are improving the resolution of subtle abnormalities of the cartilaginous structures, permitting earlier detection of abnormalities that may result in growth disturbances or articular cartilage injury. Magnetic resonance imaging techniques from ongoing research in adults are now being applied to, and have validated current research in, the cartilaginous changes in juvenile rheumatoid arthritis. These new advances in pediatric musculoskeletal magnetic resonance imaging are providing reproducible information of the cartilaginous structures and cartilage content of the immature skeleton and changes resulting from cartilage loss.

Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis

Background: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD’s). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays. Objective: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs. Methods: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis. Results: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to ‘proof of concept’ studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are ‘responder’ (or ‘failure’). The definition of a ‘failure’ patient would be someone with progression of JSN>0.5 mm over a period of 2–3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement. Conclusion: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion.

Oral treatment with PD-0200347, an α2δ ligand, reduces the development of experimental osteoarthritis by inhibiting the chondrocytes metalloproteases and inducible nitric oxide synthase gene expression and synthesis

The aim of this study was to examine the in vivo effects of PD-0200347, an α2δ ligand of voltage-activated Ca2+ channels and a member of the gabapentin family, on the development of cartilage structural changes in an experimental osteoarthritis (OA) dog model. We examined its effects on the major pathways involved in OA cartilage degradation including metalloproteases (MMPs), the inducible form of nitric oxide synthase (iNOS) and IL-1β. OA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were divided into three groups and treated orally with placebo, with 15 mg/kg/day PD-0200347, or with 90 mg/kg/day PD-0200347. Dogs were sacrificed 12 weeks after surgery. The severity of lesions was scored macroscopically and histologically. Cartilage specimens from femoral condyles and tibial plateaus were processed for quantitative PCR and immunohistochemistry. Specific probes and antibodies were used to study IL-1β, iNOS, MMP-1, MMP-3 and MMP-13 mRNA and protein levels, respectively. No clinical signs of drug toxicity were noted in the treated animals. PD-0200347 treatment at both dosages tested (15 or 90 mg/kg/day) reduced the development of cartilage lesions. There was a reduction in the score of lesions, and statistical significance (P < 0.01) was reached at the highest dosage of the drug. This score reduction was mainly related to the decrease in the lesion surface size. Quantitative PCR and immunohistochemical analyses showed that PD-0200347 treatment also significantly reduced key OA mediators, IL-1β, iNOS, MMP-1, MMP-3 and MMP-13 gene expression and synthesis. This study demonstrated the efficacy of PD-0200347 at reducing the progression of cartilage structural changes in an OA dog model. It also showed that this effect is linked to the inhibition, at the transcriptional level, of the major pathophysiological mediators. The mechanism of action could be related to a significant reduction of Ca2+ current amplitude via voltage-gated calcium channels, which in turn downregulates the downstream signaling pathways.

Mechanobiology of cartilage: how do internal and external stresses affect mechanochemical transduction and elastic energy storage?

Articular cartilage is a multilayered structure that lines the surfaces of all articulating joints. It contains cells, collagen fibrils, and proteoglycans with compositions that vary from the surface layer to the layer in contact with bone. It is composed of several zones that vary in structure, composition, and mechanical properties. In this paper we analyze the structure of the extracellular matrix found in articular cartilage in an effort to relate it to the ability of cartilage to store, transmit, and dissipate mechanical energy during locomotion. Energy storage and dissipation is related to possible mechanisms of mechanochemical transduction and to changes in cartilage structure and function that occur in osteoarthritis. In addition, we analyze how passive and active internal stresses affect mechanochemical transduction in cartilage, and how this may affect cartilage behavior in health and disease.

Joint degeneration following meniscal allograft transplantation in a canine model: mechanical properties and semiquantitative histology of articular cartilage.

This study examined the hypothesis that meniscal allograft transplantation serves a "chondroprotective" role and prevents the histological and biomechanical changes of the articular cartilage following meniscectomy. Skeletally mature mongrel dogs underwent total medial meniscectomy and received either a fresh meniscal allograft ( n=10) or no further treatment ( n=10). Semiquantitative histology and biomechanical analysis of the femoral articular cartilage was used to assess cartilage pathology 12 weeks following surgery. Histological analysis showed significant changes in cartilage structure that did not differ between the meniscectomy and allograft transplantation groups. Similarly, the tensile modulus of the surface zone cartilage was significantly lower than that in unoperated controls following either meniscectomy or allograft transplantation. A significant correlation was observed between the biomechanical and histological changes, suggesting that degenerative changes in cartilage structure and mechanical function are interrelated. Our findings do not support the hypothesis that meniscal allograft transplantation provides chondroprotection of the femoral condyle and also suggest that it does not lead to increased degenerative changes.

Characterization of enzymatically induced degradation of articular cartilage using high frequency ultrasound

Ultrasound may provide a quantitative technique for the characterization of cartilage changes typical of early osteoarthrosis. In this study, specific changes in bovine articular cartilage were induced using collagenase and chondroitinase ABC, enzymes that selectively degrade collagen fibril network and digest proteoglycans, respectively. Changes in cartilage structure and properties were quantified using high frequency ultrasound, microscopic analyses and mechanical indentation tests. The ultrasound reflection coefficient of the physiological saline-cartilage interface (R1) decreased significantly (-96.4%, p<0.01) in the collagenase digested cartilage compared to controls. Also a significantly lower ultrasound velocity (-6.2%, p<0.01) was revealed after collagenase digestion. After chondroitinase ABC digestion, a new acoustic interface at the depth of the enzyme penetration front was detected. Cartilage thickness, as determined with ultrasound, showed a high, linear correlation (R = 0.943, n = 60, average difference 0.073 mm (4.0%)) with the thickness measured by the needle-probe method. Both enzymes induced a significant decrease in the Young's modulus of cartilage (p<0.01). Our results indicate that high frequency ultrasound provides a sensitive technique for the analysis of cartilage structure and properties. Possibly ultrasound may be utilized in vivo as a quantitative probe during arthroscopy.

Investigation of the calcium content in joint cartilage: Is it connected with (early arthrotic) changes in cartilage structure?

This paper describes investigations using the Particle Induced X-ray Emission method (PIXE) to evaluate the concentration of Ca together with that of other elements (S, Cl, and K) across the articular cartilage of domestic pigs in order to verify a putative influence of calcium on the structural changes in early arthrotic stage, derived from NMR microscopic imaging. The measurements were carried out with focused ion beams of a lateral resolution down to 20 μm. The main matrix components (C, N, O) were evaluated from proton backscattering spectra.

A scanning electron microscopic study of the degenerative cartilage in patellar chondropathy

Patellar chondropathy as cartilage degeneration localized in patellar cartilage in young persons is characterized by cartilaginous changes, such as softening, swelling, and fissuring. With a view to structural characterization of early cartilaginous degeneration before erosion, the morphology of affected cartilage was studied under a scanning electron microscope. The surface network of cartilage constituting fibrils had an edematous change, presenting with fibrillation on the medial facet, whereas many fibrils of the central ridge had a collagen bundle, and fissuring of varying size was observed. It appeared that a mechanical force (shearing) acting on the site of the central ridge was associated with the formation of a collagen bundle and its destruction. On the lateral facet, fibrils were arranged perpendicular to the joint surface; the superficial layer of fibrils was worn by hyper-pressure acting on the lateral facet. On the fractured surface, the coarseness of collagen fibrils showed changes that varied with the site and stage of cartilage degeneration. Frequent changes were signs of fibril loosening (coarsening), such as reduction in fibril density (i.e., edematous change), collagen fibril aggregation, and fissuring, and longitudinal restructuring of fibrils. The patellar cartilage in the patients of this series showed a structure adapted to the mechanical force. The initial structural changes of cartilage consisted of collagen fibril aggregation and reduction in fibril density. These changes give rise to matrix rarefaction, which in turn causes cartilage degeneration to progress. These changes were concurrent in both the superficial and middle layers and were not localized as basal degeneration.