Healthy adult dogs were studied for a defect in proteoglycan aggregation by immobilizing one limb for varying periods of time. Immobilization for 6 days resulted in a 41% reduction in proteoglycan synthesis by articular cartilage from the restrained knee compared with the contralateral control knee. After 3 weeks of immobilization, proteoglycan aggregation was no longer demonstrable in cartilage from the constrained limb. The aggregation defect was rapidly reversible and aggregates were again normal size 2 weeks after removal of a cast that had been worn for 6 weeks.In normal articular cartilage most of the proteoglycans (PG) exist in large aggregates that are noncovalently linked to hyaluronic acid (HA) (1). In osteoarthritis (OA) an aggregation defect exists within the tissue, since a greater than normal proportion of the PGs is not aggregated and aggregates which are present tend to be smaller than normal (2-5).Aggregation defects similar to those of OA in
The influence of static and intermittent stress on articular cartilage metabolism was examined in vitro. Full‐thickness plugs of cartilage from femoral condyles of normal adult dogs were cultured while static or cyclic stresses were applied for 2 hours. The plugs were then incubated under atmospheric pressure for 2 hours in medium containing radioactive label, to provide measurements of net synthesis of glycosaminoglycan (GAG) or protein. As a control, cartilage from the same knee was cultured in the apparatus at atmospheric pressure. When cartilage plugs were exposed to static stress, or to cyclic stresses at a duty cycle of 60 seconds on/60 seconds off, net GAG synthesis was suppressed to 30—60% of that in controls. In contrast, when a duty cycle of 4 seconds on/11 seconds off was used, GAG synthesis was increased by 34%. The duty cycle which increased GAG synthesis did not affect protein synthesis or tissue contents of DNA, uronic acid, or water. At the cycle which suppressed GAG synthesis, protein synthesis and uronic acid content were decreased, and water content was increased. As judged by uptake of 14C‐aminoisobutyric acid and 14C‐xylose, the above changes in GAG synthesis do not appear to have been due to changes in diffusion of nutrient molecules through the cartilage during loading.
Articular cartilage from the knees of 4 dogs whose ipsilateral paws had been transected 6 weeks earlier (knee,,,,,), and from their contralateral knees (knee,,), was examined. Knee,,,,, did not bear weight as a result of the surgical procedure but active motion of the joint, determined with an angular displacement monitor during walking, was comparable to that of knee,,.. In comparison to knee,, cartilage, knee,,,, samples showed decreases in thickness, Safranin-0 staining of the matrix, and uronic acid content (mean, 24.4%), and increase in water content (mean, 5.9%). Incorporation of into proteoglycans was 34-67% less in knee,,,,, than in knee,,, cartilage. Proteoglycan (PC) aggregation in knee,, cartilage was normal, whereas in knee,,... cartilage the bulk of the proteoglycans, and also those that had been newly synthesized ('5S-proteoglycans), did not exist in aggregates. This defect in aggregation was due, at least in part, to an abnormality in the hyaluronatebinding region of the core protein of the proteoglycans, since they did not interact in vitro with hyaluronic acid These changes are essentially identical to those shown
The effect of vigorous exercise on the reversibility of canine knee cartilage atrophy produced by immobilization OF the leg was studied. In comparison to cartilage from the contralateral control knees, cartilage from knees which had been immobilized in a cast For 6 weeks showed an increase in water content and decreases in thickness, Safranin 0 staining of the matrix, uronic acid content, and net proteoglycan synthesis. In addition, the ability OF both newly synthesized (3'S) and total tissue proteoglycans to interact with hyaluronic acid to Form aggregates was diminished; this was apparently due to an abnormality in the hyaluronate-binding region of the core proteins. If the casts were removed and the animals were then allowed to ambulate ad libitum for 3 weeks, a11 of these changes were reversed. However, knee cartilage from 3 dogs which had been run daily on a treadmill (6 miledday) for 3 weeks after removal of the casts exhibited continuing decreases in thickness, Safranin 0 staining, and uronic acid content (mean 31%), even though net proteoglycan synthesis was increased (mean 16%) in comparison to that in control cartilage from the contralateral (nonimmobilized) knee. Further- more, the abnormality in both 35!3-and total tissue proteoglycans which precluded their interaction with high molecular weight hyaluronic acid persisted. In this respect, the proteoglycans were indistinguishable from those obtained from knee cartilage immediately following 6 weeks in a cast.A number of reports have detailed the morphologic features of the degeneration that occurs in articular cartilage with immobilization of a limb (1-5). Few studies, on the other hand, have focused on the alterations in articular cartilage proteoglycans (PG) that result from immobility (6-7). In normal joint cartilage, most PG exist in large aggregates, in which a number of PG are noncovalently associated with a single filamentous molecule of hyaluronic acid (HA) in a linkage stabilized by tissue glycoproteins (8). PG account for most of the elasticity ofjoint cartilage and for its ability to resist compression (9). The biologic function of the aggregate has yet to be defined, but by virtue of its enormous size (over50 x ddtons) (lo), it presumably serves to contain the PG within the collagen meshwork of the cartilage.We have recently shown that the atrophy of knee cartilage which develops when the hind limb of a normal adult dog is immobilized in a cast for 6 weeks is accompanied by decreases in uronic acid content and net PG synthesis (7). Furthermore, newly synthesized PG from cartilage of the immobilized limb did not aggregate in vitro, due to an apparent abnormality in the HA-binding region of the PG core protein (7). All of these effects of immobilization were rapidly reversible if the casts were removed and the dogs were then allowed to ambulate ad libitum "on all fours" for 3 MATERIALS AND METHODSSource of tissue and procedure for immobilization and exercise. The right hind limbs of 7 adult mongrel dogs (25-30 kg) were immobilized against t...
The effects on proteoglycan metabolism and aggregation of several nonsteroidal antiinflammatory drugs commonly used in the treatment of arthritis were examined in cultures of normal canine articular cartilage. Fenoprofen and ibuprofen inhibited net proteoglycan synthesis in a concentration-dependent fashion. A t concentrations in t h e culture medium comparable to plasma concentrations seen in patients after oral administration in humans, net proteoglycan synthesis in the presence of these drugs averaged 72% and 86% of the control values, respectively (P c 0.01).In contrast, indomethacin and sulindac sulfoxide had no effect on proteoglycan synthesis, while sulindac sulfide stimulated synthesis in a non-concentration dependent fashion (average, 13%). In the presence of ibuprofen or sulindac sulfide, catabolism of sulfated glycosaminoglycans was the same as that in control cartilage, while fenoprofen decreased the rate of degradation slightly. The proportion of newly synthesized proteoglycans existing as aggregates and the average hydrodynamic size of disaggregated proteoglycans were unaffected by ibuprofen, indomethacin, sulindac sulfide, or sulindac sulfoxide.
The in vivo effect of aspirin on degeneration of knee cartilage in a canine model of osteoarthritis was examined. When dogs were fed aspirin daily after anterior cruciate ligament transection, the degeneration of articular cartilage in the unstable knee was more marked 9 weeks later than that in the operated knee of dogs which did not receive aspirin. Compared with samples from the contralateral knees, the thickness of articular cartilage in the operated knees of aspirin-fed dogs was reduced, while it was increased in the operated knees of dogs not fed aspirin. In addition, the proteoglycan (uronic acid) content and the augmentation of proteoglycan synthesis in cartilage from the unstable knee were significantly lower when the dogs were fed aspirin than when they were not, and Safranin-0 staining of the matrix was less intense. However, cartilage from the contralateral knees of aspirin-fed dogs was histochemically and biochemically normal in every respect. When metatarsal bones, with their overlying articular cartilage intact, were cultured in the presence of 10-4M and lO-'M salicylate, net glycosaminoglycan synthesis was suppressed by 25% and 15%, respectively. These concentrations of salicylate had previously and KENNETH D. BRANDT been shown to have no effect on glycosaminoglycan metabolism in normal cartilage from the weightbearing region of the femoral condyle. Since the uronic acid content of metatarsal cartilage is lower than that of femoral cartilage, and that of osteoarthritic femoral cartilage is lower than that of normal femoral cartilage, the present results are consistent with the concept that cartilage is more permeable to aspirin when its matrix is depleted of proteaglycans.When 10-3M salicylate is added to the culture medium, glycosaminoglycan (GAG) synthesis in slices of normal articular cartilage from habitually loaded regions of canine femoral condyles is reduced by about 30%, while lower concentrations of the drug have no effcct (1,2). Notably, this in vitro inhibition of GAG synthesis by salicylate is much greater in osteoarthritic (OA) than in normal cartilage (3). Furthermore, salicylate may affect articular cartilage in vivo as well as in vitro; when aspirin was fed to dogs in quantities sufficient to achieve a serum salicylate concentration of 20-25 mg/dl (i.e., approximately lO-'M), the degeneration of femoral articular cartilage caused by immobilization of the leg was aggravated (4). Thus, knee cartilage from the constrained legs of the aspirin-fed dogs showed decreases in uronic acid content and net GAG synthesis and an increase in extractability of proteoglycans (PG), which were significantly greater than those seen in atrophic cartilage from the immobilized knees of dogs which did not reccive aspirin. However, aspirin had no apparent in vivo effect on articular cartilage of the contralateral (nonconstrained) knees.Since the PG content of OA cartilage and atrophic cartilage is lower than that of normal carti-
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.