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Effects of SL-1010 on the experimental osteoarthritis (OA) produced by intra-articular injection of papain, proteolytic enzyme, in the knee joint of the guinea pigs were histologically and biochemically investigated. In addition, experimental conditions to produce OA in guinea pig knee joint were also examined, since papain-induced OA has been mainly studied in rabbits. Six weeks after intra-articular injection of papain (1%, 0.1 ml), there were inflammatory reactions of the synovial membrane, degenerative changes in chondrocytes and the matrix of the articular cartilage, a decrease in the Safranin-O staining intensity and lowering of sulfated glycosaminoglycan. Electronmicroscopic observations revealed that the amorphous layer had disappeared and large bundles of unit collagen fibers and larger collagen fibers had appeared in the cartilage matrix. In the OA model, SL-1010 reduced the inflammatory reactions of the synovial membrane, inhibited development of degenerative changes in chondrocytes and the matrix of the articular cartilage and recovered the Safranin-O staining intensity. The sulfated glycosaminoglycan contents in the cartilage was significantly increased in the SL-1010-treated group, compared with the control group. The electromicroscopically observed charges in the papain-injected knee joint of the control group were rarely detected in the SL-1010-treated group. These results suggest that SL-1010 inhibits degenerative changes in the chondrocytes and the matrix probably by reducing synovial inflammation and protection of the cartilage in the OA model of guinea pigs.

Human recombinant interleukin-1 alpha or beta was injected intraarticularly several times into the knee joints of rats and hens at different dosages (50-2000 ng) and intervals. No loss of cartilage detectable by width of the radiological joint space and no degenerative changes of subchondral bone could be observed during 16 weeks using X-ray analysis. The macroscopical examination of articular cartilage of hens after this period and of rats after one year showed no morphological cartilage damages. These data suggest that human recombinant Il-1 alpha and beta alone may not be sufficient to induce a progressing osteoarthritic process in these animals.

Rabbit knee joint osteoarthritis was induced by intraarticular injections of a 10% sterile NaCl solution. Within 30 days the synovial membrane had undergone hyperplasia resulting in activated synovial fibroblasts. Transitional forms of synoviocytes as well as activated synovial macrophages were a very common finding. At 60 days a thickening of the synovial intima was perceptible. Most of the synoviocytes were of the fibroblast type. Transitional cell forms abounded. An increase in collagen fibres and capillaries of the fenestrated type occurred in the intercellular spaces. In the deep layer collagen bundles had formed between which activated fibroblasts and macrophages were noticed. The described changes point to an active participation of the synovial membrane in the destruction of articular cartilage in osteoarthritis.

Over 1000 workers of hydrofluoric and cryolite enterprises and electrolysis shops of aluminium enterprises were examined. Subjects exposed to soluble hydrofluorides presented in the early stage of chronic intoxication with a variety of syndromes, that was characteristic of intoxication with poisons of general toxic action with involvement of hepatobiliary, digestive, circulatory and autonomic nervous systems. Combined exposure to fluoric compounds, heating microclimate and electromagnetic fields results in a graver involvement of the circulatory and autonomic nervous systems. Clinical and experimental data show, that osteoarthrosis deformans of the major joints (primarily elbow joint) must be regarded as one of the symptoms of fluorosis, when other intoxication signs are present.

Previous studies on osteoarthritic changes induced by intraarticular injections of estradiol benzoate (EB) suggest estrogen as a risk factor in the development of knee osteoarthritis (OA). The present study observed the anti-arthritic effects of tamoxifen (TMX). Oophorectomized rabbits were subjected to intraarticular injections of vehicle control, EB, TMX, or EB/TMX for 3 weeks. The cartilage changes were assessed by light and scanning electron microscopic examination, enzyme histochemical analysis, and the amount of alcian blue stain binding to glycosaminoglycans. EB injections resulted in cell necrosis, chondrocyte clonings, and pittings, whereas the vehicle control, TMX, and EB/TMX-injected groups showed no histologic abnormalities. Histochemical analysis showed that the numbers of lactate dehydrogenase (LDH)-reactive chondrocytes in the EB-injected group were significantly reduced when compared to other groups (p less than 0.001). The injections of EB/TMX significantly reduced the chondrocyte numbers in the lateral superficial layer (p less than 0.05), compared with the vehicle injection. TMX-injected group revealed slight although insignificant decreases in chondrocyte numbers. The amount of alcian blue stains, representing the relative amount of proteoglycans, significantly decreased only in the superficial layer of the EB- and EB/TMX-injected groups (p less than 0.05). TMX, when concurrently injected with EB, antagonized the chondrodestructive effects of estradiol at the early stage of knee OA in rabbits. The results suggest the potential therapeutic use of TMX at the early stage of OA.

Aminophenyl mercuric acetate (APMA)-activated collagenase (C) (60 U/ml) obtained from in vitro cultures of human skin fibroblasts or recombinant interleukin-1 beta (IL-1 beta) (200 U/ml) was infused continuously for 7 days into the rabbit knee synovial space by means of an implanted Alzet osmotic pump. In stability studies in vitro, activated C or IL-1 incubated for 7 days at 37 degrees C, showed no significant loss of biological activity. Alterations in knee cartilage morphology and proteoglycan (PG) content were determined histologically, and the incidence of cartilage damage calculated. C or IL-1 vehicles infused for 7 days, caused no damage. Incidences of damage for C or IL-1 (n = 8-9), respectively, were as follows: loss PG: 88% and 100%; chondrocyte disorganization and loss, 50% and 78%, fissures and or fraying, 25% and 78%; and convergence of inflammatory cells, 25% and 66%. These results confirm the important role of C and IL-1 in cartilage damage.

The occurrence of the degenerative changes of the hip, knee, elbow and spine was assessed in 1598 aluminium workers. Their average age was 43.1 years and the period of fluoride intoxication was average 17.0 years. The aging process was found to be predominant factor in the development of degenerative changes. An increased prevalence of changes was found in workers with the higher exposure to fluoride. Fluoride was assumed to be one of the factors causing degenerative changes of joints.

The effect of Neurotropin on osteoarthritis was investigated in comparison with those of prednisolone and indomethacin. 1) There were remarkable decreases in the staining intensity to safranin-O and in the contents of uronic acid, total hexosamine and hexose in the articular cartilage of rabbits in which experimental osteoarthritis was induced by the injection of papain into the knee joint. In the Neurotropin-treated group, the decrease in the staining intensity to safranin-O and the contents of uronic acid, total hexosamine and hexose were evidently recovered. On the other hand, in the prednisolone- or indomethacin-treated group, the degeneration of the cartilage was even more pronounced than in the control group treated with papain alone. 2) Neurotropin had no effect on the autolytic degradation of cartilage, but promoted the incorporation of 14C-acetate into the proteoglycan in the articular cartilage of rabbits. 3) Both prednisolone and indomethacin inhibited the autolytic degradation and the incorporation of 14C-acetate into the proteoglycan. These results suggested that the therapeutic effect of Neurotropin on osteoarthritis may be due to the improvement of decreased proteoglycan content in the matrix of articular cartilage; and in this respect, it is different from anti-inflammatory drugs such as prednisolone and indomethacin.

Osteoarthrosis of the rat knee joint was induced successfully by intra-articular injection of 2% hydrogen peroxide (H2O2) and running load. In the group receiving two injections of physiological saline with running load, no histological osteoarthrotic knees were developed up to 8 weeks after the injection. In the group receiving two 2% H2O2 injections and running load, advanced osteoarthrosis occurred in all knees 8 weeks after the first injection, and the Mankin's score of osteoarthrotic knees appeared to be higher than the group receiving two 2% H2O2 injections without running load (p less than 0.004, Kruskal-Wallis H test). In the rats receiving a single 2% H2O2 injection with running load and a vitamin E-enriched diet, the inhibitory effect of vitamin E on the development of osteoarthrosis was statistically significant compared to the regular diet group (p less than 0.05, Wilcoxon rank test).

A standardized pharmacological model of biochemically induced osteoarthritis in the knee joint of laboratory animals was used for the study of a possible antidegenerative effect of ademetionine (S-adenosyl-methionine, active substance of Gumbaral) in-vivo. Four days after the initial induction of osteoarthritis by 2 intraarticular injections of 0.6 mg sodium iodoacetate into the left knee joint of adult hens, the therapy started with once-weekly intraarticular doses of 0.5 mg, 1.0 mg and 2.0 mg ademetionine over a period of 14 weeks. Quantitative monitoring of the intensity and progression of osteoarthritis was performed every 2 weeks by joint space measurements, topographic-radiological evaluations, and by a macroscopic post-mortem assessment of the joint cartilage and bone. These objective analytical parameters clearly demonstrated that weekly intraarticular doses of 1.0 mg ademetionine significantly reduced the intensity of degenerative processes compared to the placebo (saline) treated joints. The antidegenerative effect of doses of 0.5 mg or 2.0 mg ademetionine were less pronounced and of no statistical significance. Our findings indicate an interesting therapeutic potency of ademetionine in experimental osteoarthritis and confirm the positive clinical observations as well as in-vitro results with this new drug by other researchers.

Female participants of the Framingham Osteoarthritis Study (n = 831, mean age 73, age range 63-93) were evaluated for osteoarthritis with weight-bearing radiographs of the knee during 1983-1985. At each biennial examination (1963-1981), the women were asked about their use of estrogen during the previous 2 years. We categorized estrogen use as no use reported, use reported at 1 examination, or use reported at 2 or more examinations. We found no positive association of estrogen use with radiographic knee osteoarthritis after controlling for age, body mass index, age at menopause, physical activity, history of knee injury, and smoking. In fact, a modest but nonsignificant protective effect for both radiographic osteoarthritis (odds ratio 0.71, 95% confidence interval 0.42, 1.20) and severe radiographic osteoarthritis (odds ratio 0.66, 95% confidence interval 0.33, 1.32) was seen in women who reported estrogen use at 2 or more examinations. Subgroup analyses also showed no association between estrogen use and radiographic knee osteoarthritis. We conclude that estrogen use in women is not associated with an increased risk of radiographic knee osteoarthritis.

A single intra-articular injection with bacterial collagenase in the right knee joints of 10-week-old male C57bl10 mice led to osteoarthritic lesions within a few weeks in these joints. The collagenase-induced osteoarthritis was characterized by severe degenerative cartilage lesions on the medial side of the femorotibial joint associated with patellar dislocation to the medial side of the joint, sclerosis of subchondral bone below the cartilage erosions, osteophyte formation, and consequent deformity of the knee joints. The osteoarthritic alterations in the collagenase model closely resembled the changes observed in spontaneous osteoarthritis in aged mice. The intra-articular injection with collagenase probably results in damage to collagen type I-containing joint structures, such as tendons, ligaments and menisci, leading to an instable knee joint that results in the osteoarthritic joint lesions observed in this model. The collagenase-induced osteoarthritis model offers the possibility of studying experimental osteoarthritis in large animal groups of inbred strains within a restricted time span at low costs.

Male, 10-week-old C57B1 10 mice received a single intraarticular injection in the knee joints with papain, iodoacetate, or collagenase. This led to osteoarthritic lesions, such as matrix depletion, chondrocyte proliferation, and osteophyte formation, in the injected knee joints within several weeks. After injection of iodoacetate and papain, the main osteoarthritic alterations were localized in the femoropatellar joint, whereas injection of collagenase led to marked osteoarthritic lesions in the femorotibial joint. The mechanism of induction of these alterations appears to differ for iodoacetate and papain on one site and collagenase on the other site. Data are presented that collagenase injection, by way of damaging ligaments and tendons, destabilizes the knee joint eventually leading to osteoarthritic alterations. In contrast, injection of papain or iodoacetate directly interferes with cartilage metabolism resulting in osteoarthritic changes.

The effect of a 4% supplement of cholesterol to a standard diet on knee joints and vertebral columns was investigated in male mice of strain C57B1. The experimental diet was fed from the time of weaning through the 18-month period of observation or from the age of 1 year to the end of the experiment at 18 months of age. The incidence of osteoarthrosis was increased in mice fed cholesterol from the age of 12 months on. The incidence of spondylosis was increased after lifelong feeding as well as after feeding of cholesterol during the second year of life. This increase involved both, spondylosis associated with or uncomplicated by prolapse of intervertebral discs. The incidence of simple disc prolapse was not affected by the experimental diet.

We have previously shown that immobilization protects against the development of mechanically-induced osteoarthritis following-anterior cruciate ligament transection in dogs. Herein, we examine the effect of immobilization of the leg on the chemically-induced degeneration of femoral articular cartilage caused by intraarticular injection of iodoacetate in guinea pigs. One week after the injection, cartilage from animals which were not immobilized exhibited a decrease in Safranin O staining and a 10-20% reduction in the number of chondrocytes. Three weeks after injection, cell death and loss of Safranin O staining had progressed, and surface fibrillation and osteophytes had developed. Articular cartilage from the contralateral (uninjected) knees of guinea pigs which received iodoacetate, and from knees of animals which were immobilized for 1 week but did not receive iodoacetate, was histologically and histochemically normal. However, specimens from 2 of 4 untreated knees which were immobilized for 3 weeks showed a reduction in Safranin O staining. Immobilization of the knee did not alter the loss of Safranin O staining seen after intraarticular iodoacetate injection, but did reduce the depletion of chondrocytes (P less than 0.05). Furthermore, neither osteophytes nor fibrillation developed in any of the animals which were constrained after iodoacetate injection. Thus, immobilization was clearly protective in this model of chemically-induced cartilage injury.

(1) 6-week-old ICR mice were injected daily with pharmacologic doses of triamcinolone diacetate (1.5 mg/kg body weight) for 8 consecutive weeks. (2) The temporomandibular joint served as a model for histological and histochemical examinations concerning the effect of glucocorticoid hormone upon bone and cartilage. (3) Histochemical reactions indicated a large number of lipid droplets within the peripheral vasculature. (4) Histological examinations revealed pathologic features, indicative of primary osteoarthrosis.

The main purpose of this investigation was to develop a model for experimental induction of osteoarthrosis. A previously described method using papain was tried on guinea pig knee joints. Eighteen adult guinea pigs were given papain intra-articularly in the right joints; the left joints were used as controls. The animals were killed after 6 hours, 1 week, 2 weeks, 2 months, 4 months, 6 months, 8 months, and 10 months. Specimens of the articular cartilage were removed for histologic and histochemical investigation. Microscopic surface irregularities could be observed in the animals after 6 hours, 1 week, and 2 weeks, and again after 8 and 10 months. Histochemical examination of the sections from the experimental joints indicated a loss and degradation of the sulfated glycosaminoglycans. This loss was evident after 6 hours, 1 week, 2 weeks, and 8 months. The first osteoarthrotic changes were observed macroscopically after 8 months. Radiographic changes in the experimental joints could be observed in all animals killed after 10 months. It was concluded that osteoarthrosis similar to that occurring in humans can be induced by this method.

A histological and autoradiographical study on the reaction of chondrocytes and the growing processes of osteophyte after the intraarticular injection of papain was carried out. The degenerating processes--fibrillation, death of chondrocytes and erosion--were observed as early as 1 day after the injection, and acid mucopolysaccharide staining with safranin-O was completely lost throughout the articular cartilage 1 week after the injection. The regenerating or proliferating figures--chondrocytes mitosis, thickening of fibrous tissue--were observed as early as 3 days after the injection and chondrocyte clusters were noted after 1 week of injection. Four weeks after injection, proliferating processes were more obvious than degenerating processes, safranin-O stainability had recovered and the proliferative figures of cartilage and fibrous tissue became more obvious. As blood vessels invaded into the cartilage and thickened fibrous tissue, osteophyte began to form in these tissues. Four types of growing processes of osteophyte were observed. Hypertrophy of articular cartilage was observed, and new hyaline articular cartilage appeared to be formed through metaplasia from fibrous tissue. Including the osteophyte formation, tremendous regenerating or repairing efforts of chondrocytes and fibroblasts were observed. These results appear to indicate that cartilage has some ability to regenerate and to repair itself if it could avoid further damage.

A chemically-induced joint degeneration was produced by an one-time intraarticular injection of the glycolysis inhibitor monoiodic acetate into the rabbit knee joint (32 joints of 16 rabbits + 4 control animals). The investigation is founded on Kalbhen's animal model of osteoarthrosis and on Salter's and Moskowitz' experiments. Histomorphological examinations were done in intervals of 1 day to 12 weeks. The results raise several open questions in experimental as well as clinical aspects. On that account these results were discussed pathogenetically in the view of the own pathophysiological and biocybernetical conception of osteoarthrosis development.

For pharmacological testing of drugs with antidegenerative potency we developed an animal model of biochemically induced osteoarthritis (OA) by blocking the glycolytic energy metabolism and synthetic processes in articular chondrocytes. After local injection of sodium iodoacetate osteoarthritic reactions will progress within 2-4 months. Using a standardized radiological, histological, and macroscopical grading we could demonstrate that corticosteroids and some NSAID exert negative effects on articular cartilage, while a few other NSAID showed no influence. Diclofenac had even a pronounced antidegenerative potency which was comparable to the antiosteoarthritic properties of two glycosaminoglycan derivatives investigated in the model of biochemically induced OA in the knee joint of hens and rats.

Single intra-articular injections of copper II bisglycinate [Cu(II)gly] (30-300 micrograms) into guinea-pig knee joints induce progressive joint degradation which first appears after about 2 weeks and peaks about 12 weeks after injection. The stable complex, copper II bishistidinate (300 micrograms) was without effect. The Cu(II)gly induced syndrome has features more in common with osteoarthritis than rheumatoid arthritis in that erosion occurs in the absence of persistent synovial inflammation. The possibility that the damage may be caused by Cu(II)gly inducing free radical formation within the joint, leading to a self-perpetuating chain reaction is discussed. D-Penicillamine and other drugs were tested for their effects on the histological changes induced 4 weeks after the intra-articular injections of 100 micrograms Cu(II)gly. Few significant effects were observed and these were restricted to D-penicillamine, which caused inconsistent protection, sodium aurothiomalate which protected at a dose causing weight loss and prednisolone which exacerbated joint damage. It is concluded that the variability of the control response will need to be reduced before the model can be used for routine drug evaluation but it may be of value in the study of chronic degradative joint disease.

In experiments on rabbits the authors studied the dynamics of cartilage degeneration and subsequent pseudorepair processes following what was doubledose chemical damage to articular cartilage. In addition to the classical histological methods they used the histochemical demonstration of hydrolase and dehydrogenase which are of prime importance to cartilage. The intraarticular instillation of sodium iodacetate caused major and irreversible damage to the whole cartilaginous layer. Subsequent pseudorepair proceeded on the one hand from the cells of the peripheral synovial membrane and on the other to a lesser extent from the fibroblasts of the subchondral bone marrow. The most important enzymes depicting these processes can be regarded as AP and LDH. From the viewpoint of accessibility of dystrophic articular cartilage to repair cells one must distinguish the central part of the joint from its periphery. In the latter area of the cartilage it were mainly synovial cells which took part in repair and pseudorepair takes place considerably more actively here than in the central parts of the joint.

Changes in the extracellular components of various connective tissues with time and continuous use, as well as within experimentally-induced and human pathological conditions, were studied by morphological, chemical and biochemical methods. Osteoarthrotic lesions were produced surgically by implantation of polyethylene sheets, by continuous compression of the knee joint, and by intraarticular papain injection. Results of the model experiments showed that, irrespective of the method used for the production of experimental cartilage lesions, the alterations are strikingly similar. Within connective tissues a gradual deterioration takes place, as measured by marked differences in the histological and histochemical patterns. The degradative changes occur primarily in the matrix, resulting in a significant decrease in proteoglycan content. Under conditions of stress, in young animals, chondrocytes seem to revert to the chondroblastic state, showing mitotic figures, and are capable of producing matrix much more rapidly than is normally seen. This increased activity might be regarded as a nonspecific "feed-back" response of cells, leading to a reparative normalization of the various destructive tissue alterations.

The author has reviewed the changes in the patello-femoral joint seen on plain films in 41 male alcoholics. These are due to the effect of hyperlipoproteinaemia type IV on the patello-femoral joint. These joints show bilateral secondary arthrosis. At the same time as these erosions and defects of the articular surface develop, there are also changes in the femoro-tibial joint.

Immature A/J mice were treated for up to seven weeks with intermittent systemic doses of triamcinolone hexacetonide (4 mg/kg body weight) and were than allowed to recover for seven weeks. Morphological studies were performed on the mandibular condylar cortilage of treated and control animals. By the third dose, obvious structural changes were seen within the cartilaginous matrix. The latter appeared first in the midst of the condylar cartilage and, in the more severe cases, also involved the articular surface. The hormonal catabolic influence intensified progessively so that by the end of the experimental period, most condyles had undergone severe degenerative changes in the form of cartilage fibrillation and ulceration. After the recovery period, experimental condyles had regained their normal appearance. Thus, although intermittent systemic administration of corticosteroid hormone tends to induce osteoarthritic changes in the mandibular joint of the mouse, the mice possess the capacity to undergo full recovery shortly after the termination of the hormonal treatment.

We investigated biochemical modifications of the initial phase of cartilage degradation in an osteoarthritic model developed in the rabbit by intraarticular papain injection. The amino-acid composition of the collagen did not differ significantly between control and papain-treated groups. After 3H-proline in vivo incorporation, the absence of radioactivity in peaks beta 12 and alpha 2 shows that cartilage did not synthesize type I collagen in noticeable quantity during the labelling period. The study of proteoglycans by the use of the "fixed charges density" (FCD) shows that in our model they decreased rapidly and substantially, as in human disease. The decrease was measurable from 1 h after injection with a minimum at about 24 h (54% of the normal level). However, increased 35SO4 incorporation was observed, beginning very soon after injection and passing through a maximum (500% of the normal level) around the 3rd day. The rates of 3H-proline incorporation and 3H-hydroxyproline formation were decreased in the treated cartilage in a similar way as for the proteoglycans, with a minimum (55% of the normal level) at about 24 h. The "turn-over" of 3H-hydroxyproline and "non collagen" 3H-proline were increased in the treated cartilage. The half-lives of both amino-acids went respectively from 26 to 15 days and from 14 to 10 days. Injection of papain in the rabbit knee-joint produced a major loss of ground substance and a reaction of the chondrocytes. The cells metabolism seemed modified with especially a catabolism stimulation.

Animal experiments have shown that weekly intraarticular injections of various antiphlogistic/antirheumatic drugs into the knee joint induce progressive degenerative alterations in joint cartilage. The observed degenerations and destructions are most similar to the pathophysiology of osteoarthrosis in humans. By X-ray and macroscopic techniques the degenerative processes can be studied qualitatively and quantitatively. A decrease of joint space is a sensitive and early indicator of osteoarthrosis and showed that 10 weeks after intraarticular application of Ibuprofen, Phenylbutazone, Oxyphenbutazone, Flufenamic acid, Niflumic acid, Na-salicylate, Clofezone, Bumadizone and Dexamethasone the degenerative alterations in the injected knee joints were more severe than by applications of Chloroquine,D-penicillamine, Salicylamide and Indometacin. The degenerative effect on articular cartilage by the investigated drugs can be explained by their inhibitory potency on anabolic metabolism of connective tissue. The results of our animal experiments lead to the conclusion, that antiinflammatory drugs may also in man induce or accelerate degenerative joint diseases especially after long term treatment with high doses of these drugs.

A 56 year old man was seen because of recurrent right shoulder hemarthroses and a superior vena caval syndrome. Intermittent symptoms had occurred for six years and resulted in marked destructive changes in the right shoulder. Arthroscopy added pathological evidence of this unusual mechanism of arthropathy. Patients on anticoagulants deserve close attention to symptoms of occult bleeding.

Fifty-two adults and 31 children, who were treated with osmic acid for one knee joint, were observed for 8-18 years. No other local treatment of the knee joints was given. In adults no difference was seen in clinical or radiological findings between joints treated and not treated with osmic acid. The age of the patient had a marked influence on the development of degenerative joint disease. In children, radiological deterioration of the knee joints was marked in joints affected by radiological changes even before treatment. It is concluded that though osmic acid causes superficial damage to the cartilage, it has no significant clinical relevance. Osmic acid can still be recommended as a simple remedy in the treatment of knee joint synovitis, in both adults and children.

The data on oral contraceptive use and arthritis in the Oxford-Family Planning Association contraceptive study have been analysed. For rheumatoid arthritis, the rate of first referral to hospital was 0.33 per 1000 woman-years in those who never used oral contraceptives (27 cases), 0.33 per 1000 woman-years in ex-users of oral contraceptives (29 cases) and 0.44 per 1000 woman-years in current users of oral contraceptives (22 cases). Likewise, there was no important association between oral contraceptive use and other forms of arthritis. An unexpected finding was a strong association between referral to hospital for rheumatoid arthritis and cigarette smoking; the rate in women never smoking was 0.27 per 1000 woman-years (34 cases) and in those smoking 15 or more cigarettes per day was 0.64 per 1000 woman-years (19 cases).

Rapidly progressing joint disease can be produced in the rabbit by intra-articular injection of concentrated papain. With the use of radioactive thymidine it is possible to demonstrate that the cartilage cells recover their ability to divide by mitosis at the same time as degenerative changes appear in the cartilage. Clusters of chondrocytes arise by mitosis of chondrocytes and not by a floating together of cartilage cells.

The integration of immature cartilage allografts to knee joints of both normal rabbits and those submitted to arthritis through papain was studied for a period of up to 9 months. Two types of grafts were compared: chondral--constituted only by cartilage, and osteochondral--cartilage plus a thin layer of subchondral bone. The integration of the grafts was analyzed through inspection of the articular surface and histologic sections. The viability of the grafts was checked through the incorporation of 35SO4 on the chondral matrix. The following conclusions were drawn: (1) A large member of the grafted cartilages were well accepted without histological evidence of immunological rejection, and metabolically active 9 months after transplantation. (2) The chondral graft was found to be superior to the osteochondral one regarding the integration, but both showed tendency to degeneration with time. (3) The presence of arthritis previously induced by papain affected the integration of the grafts causing a higher precentage of degeneration on the grafts causing a higher precentage of degeneration on the grafted cartilage.

Starting from Bentley's works [2], we elaborated an experimental model of arthrosis easy to use, providing reproducibility of effects and showing the same development as the human disease, but within a far shorter time. Papain injection induced a quick, high loss in proteoglycans. A rapid, localised chondrocyte reaction in the middle layer of the support area was noted. In this area, cells rapidly showed hyperactivity signs and a crown of microfibers taking the amyloid tissue-specific staining was seen around them. The building of such crowns might result from a discrepancy between collagen and proteoglycan secretion inducing a modification in their inter-relations. We also noticed binucleate cells, someones being in process of division, which might be the beginning of clones.

Osteoarthrosis is characterized in the early stages by degradation of articular cartilage matrix. Clinical, radiological, and pathological studies have failed to reveal the factors which initiate the breakdown of cartilage and are not applicable to detailed sequential studies of the affected tissues at all stages in the disease. Therefore animal experiments have been employed to provide more information on degradation and repair process in cartilage. These studies have demonstrated: 1) Matrix protection and induced repair of mature articular cartilage by the use of oral aspirin after lacerative injury. 2) Establishment by the intra-articular injection of the plant enzyme papain of a model of osteoarthrosis in the rabbit hip which mimics human osteoarthrosis and is suitable for further experimental studies. 3) A proliferation of mature articular cartilage chondrocytes in response to loss of matrix, which indicates a latent repair capacity. 4) Repair of extensively damaged hip joints after femoral osteotomy by increased formation of subchondral new bone and formation of fibrocartilage on the articulating surfaces. These tissue repair processes are associated with an increase in vascularity of the femoral head and acetabulum produced by the osteotomy. 5) Succesful transplantation as allografts in both normal and arthrotic rabbit knees of aggregates of epiphysial chondrocytes isolated from their matrix. This method of joint surface replacement may have clinical applications.

Basing on the fact that in adult articular cartilage there is an equilibrium of anabolic and catabolic processes, we developed a hypothesis that an experimentally induced reduction of anabolic reactions will lead to degenerative alterations in joint cartilage. In our experiments using monoiodine acetate, a potent inhibitory substance, we could confirm that 6-8 weeks after intraarticular injection into the knee joint of hen arthrotic processes can be observed in cartilage. By macroscopical, histological and biochemical criteria these arthrotic degenerations are in good correlation with human osteoarthrosis. Our new experimental model of osteoarthrosis in laboratory animals appears to be very sutiable for the study of degenerative articular processes and for pharmacological tests of new antiarthrotic drugs.

Systemic corticosteroid treatment induces morphological and functional changes in the articular cartilage similar to those in human osteoarthritis. In animal experiments the dexamethasone-induced inhibition of chondrocyte metabolism can be reduced in a dose-related manner by concomitant treatment with glycosaminoglycan-peptide complexes (GP-C)***). The metabolic changes in cartilage tissues of the joint and Processus Xiphoideus measured quantitatively by 35S-sulphate incorporation are comparable. The results indicate that GP-C could also have a dose-related effect on human osteoarthritic cartilage.

A large number of experimental data have given evidence that many NSAIDs can inhibit the synthetic processes of connective tissue in-vitro and ex-vivo. During the past 18 years we have investigated the in-vivo effect of antirheumatic drugs on knee joint cartilage using rats and hens. Single or once-weekly intraarticular injections of salicylates, indomethacin, phenylbutazone, naproxen, ibuprofen, clofezone, fufenamic acid, niflumic acid, or dexamethasone induced morphological alterations in the joint cartilage and subchondral bone, which were demonstrable by means of histology, stereoelectron-microscopy, biochemistry and X-ray. The cartilage of these laboratory animals had a faster turnover compared to man, and the degenerative and destructive processes occurred within 8-12 weeks and were identical or very similar to osteoarthritis in man. In contrast to the general opinion that all NSAIDs possess more or less the same pharmacological properties, the influence of these drugs on articular cartilage was, surprisingly, quite different. In our animal experiments we found that comparable doses between NSAIDs, such as fenbufen, ketoprofen, diclofenac, and tiaprofenic acid, did not induce any degenerative processes in cartilage and subchondral bone in-vivo. A documentation of our radiographical, macroscopical and histomorphological results demonstrated the pronounced differences between NSAIDs on joint tissue. Our experimental data suggested that in the pharmacotherapy of osteoarthritis a specific selection of NSAIDs between those with catabolic and those with non-catabolic characteristics in regard to connective tissue metabolism was important and beneficial.