Effects of diclofenac, aceclofenac and meloxicam on the metabolism of proteoglycans and hyaluronan in osteoarthritic human cartilage

1. Since nonsteroidal anti-inflammatory drugs (NSAIDs) may impair the ability of the chondrocyte to repair its damaged extracellular matrix, we explored the changes in the metabolism of newly synthesized proteoglycan and hyaluronan (HA) molecules produced by aceclofenac, diclofenac and meloxicam in human osteoarthritic (OA) cartilage. 2. Explants were sampled from the medial femoral condyle and were classified by use of the Mankin's histological-histochemical grading system. Cartilage specimens exhibited moderate (M) OA in 20 subjects and had severe (S) OA in 20. 3. Cartilage explants were pulsed with [-3H]-glucosamine and chased in the absence or in the presence of 0.3 - 3 microg ml(-1) of either aceclofenac, diclofenac or meloxicam. After papain digestion, the labelled chondroitin sulphate ([-3H]-proteoglycans) and [-3H]-HA molecules present in the tissue and media were purified by anion-exchange chromatography. 4. In cartilage with MOA and SOA, the metabolic balance of proteoglycan and HA was unaffected by diclofenac. In contrast, and in a dose-dependent manner, aceclofenac and meloxicam both increased the synthesis of proteoglycans and HA in explants with MOA and SOA; these two NSAIDs also reduced significantly the net loss of [-3H]-proteoglycans and [-3H]-HA molecules from cartilage explants. 5. The data obtained in short-term in vitro cultures indicate that, at the concentrations found in synovial fluid, aceclofenac and meloxicam may exert a favourable effect on the overall metabolism of proteoglycans and HA in cartilage with MOA and SOA.     

Tensile properties of human knee joint cartilage: I. Influence of ionic conditions, weight bearing, and fibrillation on the tensile modulus

The flow-independent (intrinsic) tensile modulus of the extracellular matrix of human knee joint cartilage has been measured for normal, fibrillated, and osteoarthritic (removed from total knee joint replacements) cartilage. The modulus was determined in our isometric tensile apparatus and measured at equilibrium. We found a linear equilibrium stress-strain behavior up to approximately 15% strain. The modulus was measured for tissues from the high and low weight-bearing areas of the joint surfaces, the medial femoral condyle and lateral patello femoral groove, and from different zones (surface, subsurface, middle, and middle-deep) within the tissue. For all specimens, the intrinsic tensile modulus was always less than 30 MPa. Tissues from low weight-bearing areas (LWA) are stiffer than those from high weight-bearing areas (HWA). The tensile modulus of the ECM correlates strongly with the collagen/proteoglycan ratio; it is higher for LWA than for HWA. Osteoarthritic cartilage from total knee replacement procedures has a tensile stiffness less than 2 MPa.     

Levels of serum keratan sulfate rise rapidly and remain elevated following anterior cruciate ligament transection in the dog.

The levels of serum keratan sulfate (KS) were measured in 9 dogs who underwent anterior cruciate ligament transection. They rose in some animals as early as 7 days after surgery, long before any decrease in the articular cartilage content of KS containing proteoglycans could be measured; and they reached their maximum in most dogs by Day 21 and remained elevated for at least 13 weeks. In contrast, the serum levels of the KS epitope showed no increase in sham operated control animals. Analysis of synovial fluid suggested an increase in the catabolism of cartilage proteoglycans in the operated joint contributed significantly to the increased levels of serum KS.     

Effects of calcitonin on subchondral trabecular bone changes and on osteoarthritic cartilage lesions after acute anterior cruciate ligament deficiency.

Because SBM may contribute to cartilage breakdown in OA, experimental OA was induced in dogs by transecting the anterior cruciate ligament of the knee and treating with either CT or a placebo. CT significantly reduced both SBM and cartilage lesions. This study supports the use of CT in the treatment of canine experimental OA. INTRODUCTION: Because subchondral bone remodeling (SBM) may contribute to cartilage breakdown in osteoarthritis (OA), we evaluated to what extend calcitonin (CT) might affect cartilage and bone changes in the early stages of canine experimental OA. MATERIALS AND METHODS: Twelve dogs underwent transection of the anterior cruciate ligament (ACLT) of the right knee. After ACLT, each animal received a daily nasal spray delivering either 400 U of CT (CT-treated group; n = 6) or a placebo (PL-treated group; n = 6). At day 84 after surgery, animals were killed, and cartilage changes were graded. BMD and volume fraction (BVF) were assessed by pQCT in different regions of interest (ROIs) of the subchondral cancellous bone of tibial plateaus (TPs).Statistics included a 2 x 2 factorial analysis with +/-CT as one factor and +/-ACLT as the other. RESULTS AND CONCLUSIONS: Nonoperated (N-OP) knees were normal in both groups. In the PL-treated group, ACLT knees all exhibited OA changes, which predominated in the medial knee compartment. Furthermore, compared with N-OP knees, the BMD and BVF of ACLT joints were both markedly reduced in medial TP but not in lateral TP. In contrast, in the CT-treated group, cartilage OA lesions of ACLT knees were significantly reduced, and there was no difference in BMD and BFV between N-OP and ACLT knees. These findings suggest that the loss of subchondral trabeculae contributes to cartilage breakdown, possibly by enhancing cartilage deformation on joint loading. By counteracting bone loss, CT reduced cartilage OA lesions, and thus, might be useful in the treatment of OA in cruciate-deficient dogs.     

Centrifugal and biochemical comparison of proteoglycan aggregates from articular cartilage in experimental joint disuse and joint instability

Two models involving altered joint loading were compared with regard to their effects on the biochemical composition and proteoglycan aggregate structure of articular cartilage. Disuse atrophy was created in greyhound dogs by nonrigid immobilization of the right knee in 90° of flexion, and joint instability was created by transection of the anterior cruciate ligament. Similarities and differences between the two experimental groups at two different time periods were examined to investigate why joint instability induces progressive and irreversible changes to the articular cartilage, whereas joint disuse induces changes that may be reversible when the joint is remobilized. The following studies were performed on the cartilage from all experimental and control groups: (a) compositional analyses to determine water, uronate, and hydroxyproline contents; (b) high performance liquid chromatography for detection of hyaluronan and chondroitin sulfates; and (c) centrifugation analyses of nondissociatively extracted and purified proteoglycans to isolate and quantify the populations of monomers and slow and fast-sedimenting families of aggregates. In general, all cartilage was found to have a decreased ratio of proteoglycan to collagen after 4 weeks of disuse, and this ratio returned to control values at 8 weeks. In contrast, cartilage had an elevated ratio of proteoglycan to collagen as well as increased hydration at 12 weeks after transection of the anterior cruciate ligament. The most striking contrast between the two models was the finding of an approximately 80% decrease in the content of hyaluronan at both time periods after transection of the anterior cruciate ligament, with no evidence of a change after disuse. The results of centrifugation analyses indicated a significant decrease in the quantity of proteoglycan aggregates in both models. However, this decrease was associated primarily with a loss of slow-sedimenting aggregates after disuse and a loss of both slow and fast-sedimenting aggregates after transection of the anterior cruciate ligament. Furthermore, the population of fast-sedimenting aggregates. The preservation of fast-sedimenting aggregates as well as hyaluronan after periods of joint disuse but not joint instability suggests a possible mechanism for the reversibility of cartilage changes. Although the proteoglycan aggregates were depleted after disuse atrophy, it is possible that an aggregate-depleted matrix could recover when normal proteoglycan synthesis is resumed. In contrast, although synthesis may be maintained or elevated after transection of the anterior cruciate ligament, the matrix may not be repopulated with aggregates because there is an insufficient amount of hyaluronan.     

Osteomalacia in hyperphosphoethanolaminuria without hypophosphatasia (author's transl)]

Increased urinary excretion of phosphorylethanolamine (P.E.A.) is one of the salient features of hypophosphatasia. This inherited disorder is generally transmitted as an autosomial recessive trait and is characterized by abnormal mineralization of bone, premature loss of deciduous teeth and reduced tissue and serum alkaline phosphatases (A.P.) levels. The authors report a series of patients presenting with pains of skeletal origin attributed to an osteomalacia syndrome on the ground of a bone biopsy. These patients had no history of rickets during childhood but complained of early severe caries of the permanent dentition before the age of twenty. They had neither malabsorption nor renal tubular abnormalities. Their serum 25 OH vitamin D was normal and their serum A.P. levels were within the normal range with a normal isoenzyme distribution. All these patients had increased excretions of urinary P.E.A. and the latter correlate significantly with the degree of osteomalacia. Control patients with a malabsorption syndrome, showing osteomalacia and serum A.P. of the same degree of magnitude as the patients of the first group, have a normal P.E.A. excretion and no correlation appears between the degree of osteomalacia and the P.E.A. excretion. The cases with increased P.E.A. excretion may correspond to adult pseudohypophosphatasia. The signification of increased P.E.A. excretion is discussed.     

beta2-Microglobulin in synovial fluid (author's transl)]

In a series of patients with rheumatoid arthritis we found higher levels of synovial beta2-microglobulin (5,2 +/- 3 mg/l) than in gouty arthritis (2,4 +/- 0,6) or osteoarthritis (1,2 +/- 0,3 mg/l). The ratio of synovial/plasma beta2-microglobulin was always superior to unity (2,3 +/- 0,7) in the R.A. patients whereas it is always inferior to unity in the other groups. The correlation between plasma or synovial beta2-microglobulin and synovial lymphocyte count was highly significant in all cases in RA patients plasma and synovial beta2-microglobulin are significantly related to the degree of joint involvement as expressed by the joint count.