Effects of salicylate on chondrocytes from osteoarthritic and contralateral knees of dogs with unilateral anterior cruciate ligament transection

Abstract

Salicylates suppress net glycosaminoglycan synthesis in articular cartilage. The inhibitory effect is greater in osteoarthritic (OA) cartilage than in normal cartilage. Whether the isolated OA chondrocyte is inherently more susceptible to the effects of salicylate on glycosaminoglycan metabolism has not been determined. The results of this study show that, after isolation from the extracellular matrix, normal and OA chondrocytes in suspension culture are similarly susceptible to the metabolic effects of salicylate. However, chondrocytes from the contralateral knees of dogs with unilateral OA were notably resistant to the effects of salicylate.Salicylates produce reversible, concentrationdependent suppression of proteoglycan (PG) synthesis by normal articular cartilage in vitro. The effect is much greater in osteoarthritic (OA) cartilage than in normal cartilage (1). Since uptake of ''C-acetylsalicylic acid by slices of OA cartilage has been shown to be significantly greater than that by normal cartilage (I), the depletion of negatively charged PGs in the matrix of OA cartilage presumably facilitated diffusion of the weakly acidic salicylate into the matrix. This possibility was supported by data demonstrating increased suppression of PG synthesis in normal cartilage after enzymatic depletion of its PGs (2).The above data do not exclude the additional possibility that in OA, the chondrocyte, which is intrinsically hypermetabolic (3,4), may be more susceptible than normal to the effects of salicylate. In the present study, we used isolated chondrocytes in suspension cultures, rather than cartilage organ cultures, to examine the susceptibility of the OA chondrocyte to salicylate. MATERIALS AND METHODSSurgical procedures. OA was induced in a standard manner in 9 normal adult mongrel dogs (25-30 kg) by transection of the anterior cruciate ligament of the right knee (1). Postoperatively, all dogs bore weight on the operated limb by the third day and ambulated freely in caged runs (4 feet x 8 feet) until they were killed 10-13 weeks later. Nine additional adult mongrel dogs that underwent no surgical procedure were used as normal controls.Tissues. At the time the dogs were killed, fullthickness samples of the articular cartilage and underlying subchondral bone were obtained from the central regions of the habitually loaded area of the medial femoral condyle of both knees of each animal for histologic study. Slices of articular cartilage (10-15 mg wet weight) were taken from the same sites for determination of dry weight and uronic acid concentration. The remainder of the cartilage from the articular surfaces of the medial and lateral femoral condyles and tibia1 plateaus was used for isolation of chondrocytes.

Increased release of matrix components from articular cartilage in experimental canine osteoarthritis

“…Although the rates of proteoglycan and collagen synthesis are increased, these events are accompanied by an increased rate of release of the newly synthesized proteoglycan from the cartilage matrix (6,35). Recently, this model has proved useful in determining effects of drugs on the development of the disease and the activity of the cartilage (36,37,39,62).Proteoglycans are a major component of the extracellular matrix of articular cartilage (20,33,45,49) and are vital in maintaining the function of the tissue. Proteoglycans of cartilage are complex glyco-…”

“…Although the rates of proteoglycan and collagen synthesis are increased, these events are accompanied by an increased rate of release of the newly synthesized proteoglycan from the cartilage matrix (6,35). Recently, this model has proved useful in determining effects of drugs on the development of the disease and the activity of the cartilage (36,37,39,62).…”

Histological features of osteoarthritic canine cartilage after prolonged administration of carprofen

“…There is also evidence that some members of this group of drugs can have deleterious effects on bone and cartilage metabolism (13,32). Some drugs, such as salicylates and indomethacin may accelerate the destructive processes in osteoarthritic joints, depending upon the drug concentration (1,29,33). These detrimental outcomes have largely been derived from in vitro experimental studies of cartilage explant cultures and, while some drugs have demonstrated a negative effect, other members of this family of drugs have been shown to possibly improve, or protect, cartilage metabolism or not to have any effect at all (5, 17, 20, 30).…”

Quantification of mechanoreceptors in the canine anterior cruciate ligament

“…Injury to these structures can result in instability and "giving out" of the knee. In the dog an ACL tear usually results in rapidly progressive osteoarthritis of the knee joint [1,4,5,7,12,13,18,19,20,23], but this progression is not necessarily true in humans [2,6,8,14,15,21,22].…”