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PubMed1989

Retardation of articular cartilage degradation by glycosaminoglycan polysulfate, pentosan polysulfate, and DH-40J in the rat air pouch model.

The rat subcutaneous air pouch model was adapted to examine the in vivo degradation of implanted rabbit articular cartilage, both with and without induced air pouch inflammation, over a 7-day period. The effects of 3 drugs, glycosaminoglycan polysulfate (Arteparon), pentosan polysulfate (SP-54), and zinc-chelated pentosan polysulfate (DH-40J), on inflammation-induced cartilage degradation were also examined. Implanted articular cartilage from noninflamed air pouches showed a reduction in total proteoglycan (PG) content (as hexuronic acid), but not in PG extractability or aggregation, compared with cartilage maintained in tissue culture. The injection of peptone into the air pouch as an inflammogen caused an influx of leukocytes and plasma exudate and a reduction in implanted articular cartilage PG content, extractability, and aggregation, which was significantly greater than that which occurred in noninflamed air pouches. In vitro experiments demonstrated that peptone did not have a direct effect on cartilage PG degradation. Daily injection of Arteparon, SP-54, or DH-40J (10 mg/kg) into peptone-inflamed air pouches significantly increased the PG content, extractability, and aggregation in implanted articular cartilage, compared with that in cartilage from non-drug-treated control animals. The infiltration of leukocytes into the peptone-inflamed air pouches was significantly reduced by daily administration of Arteparon, 10 mg/kg. At an equivalent dose, DH-40J increased leukocyte numbers in the pouch fluid, whereas SP-54 had no significant effect on leukocyte accumulation.

Animals↗
PubMed2002

Horizontally oriented clusters of multiple chondrons in the superficial zone of ankle, but not knee articular cartilage.

Osteoarthritis is a progressive disease that is initiated at the surface of articular cartilage and proceeds to destroy the entire depth of the cartilage. The prevalence of osteoarthritis varies in different joints; e.g., the ankle joint has a very low prevalence of the disease compared to the knee joint. To better understand any inherent differences between the articular cartilage of the ankle and that of the knee that would account for the difference in occurrence of osteoarthritis, studies were undertaken to examine differences between the superficial zones in these two joint cartilages obtained from human donors. Chondrocytes in the superficial zones of the normal ankle (talocrural) and the normal knee (tibiofemoral) joints were identified with a monoclonal antibody specific for the superficial zone protein (SZP). When the chondrocytes from both joints were compared in serial horizontal sections, the chondrocytes in the superficial zone of the knee cartilage were seen either as isolated single cells or as doublets. However, the chondrocytes within the superficial zone of normal ankle cartilage were arranged in planar clusters containing multiple chondrons composed of 2-13 cells. There were no detectable differences in the chondrocyte clusters in the superficial zone of the ankle with respect to age, gender, or site on the cartilage surface. Adjacent to a lesion in an ankle joint with degenerative changes, the clusters were larger, containing up to 22 chondrocytes. This is the first report documenting the presence of multiple chondrons in the superficial zone of normal human adult articular cartilage.

Adolescent↗
PubMed1992

Bone and cartilage resorption in relation to tooth development in the anterior part of the mandible in cichlid fish: a light and TEM study.

This paper presents ultrastructural features of the contact region between particular tooth germs and Meckel's cartilage prior to, during, and after initial resorption of the perichondral bone and of the cartilage in the cichlids Hemichromis bimaculatus and Astatotilapia burtoni. Imminent resorption opposite such teeth is announced by the presence, in this region, of a particular cell type, considered to be a stage in the cytodifferentiation of osteoclasts. Slightly later, an osteoclast with typical ruffled border is seen to open a fenestra in the perichondral bone which surrounds Meckel's cartilage. Although the action of the osteoclast is directed primarily towards the bone, it may also affect, to a much lesser extent, the underlying uncalcified cartilage. Typically, fibroblast-like cells invade the resorption cavity along with the osteoclast; the tooth germ soon follows. Capillaries are seen to invade the cartilage only at a later stage when a large cavity has been established. It is proposed that the fibroblast-like cells may have a dual function: degradation of cartilage and deposition of new bone. Although these processes are normally limited to the area surrounding tooth germs at specific loci, tooth germs in other positions may sometimes be seen invade the cartilage. They do so either passively, because of the existence of such a cavity, or as a result of their own resorption-inducing activity. Whatever the mechanism, attachment bone is being deposited within the erosion cavity and on the surface of the exposed perichondral bone. The stimuli possibly eliciting resorption of Meckel's cartilage are discussed. It is hypothesized that pressure exerted by the growing tooth germ may stimulate the osteoblasts covering the bone surface and, in this way, provoke osteoclastic bone resorption.

Animals↗
PubMed2003

Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis.

OBJECTIVE: To study the role of the activating Fc gamma receptor types I and III (Fc gamma RI and Fc gamma RIII, respectively) and the inhibiting Fc gamma receptor II (Fc gamma RII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune complexes. METHODS: Immune complex-mediated arthritis (ICA) was passively induced by lysozyme-antilysozyme complexes in Fc gamma RI-, Fc gamma RIII-, and Fc gamma RII-knockout mice and their wild-type controls. Total knee joints were isolated to study inflammation and cartilage destruction (loss of proteoglycans [PGs], chondrocyte death, matrix metalloproteinase [MMP]-mediated neoepitope [VDIPEN] expression, and erosion). The presence of an active phenotype of macrophages was studied by detection of myeloid-related proteins 8 and 14 (MRP8 and MRP14, respectively). RESULTS: Influx and activation of inflammatory cells (MRP expression) during ICA was decreased in Fc gamma RIII-deficient mice and enhanced in mice lacking Fc gamma RII. Mild cartilage destruction reflected by loss of PGs was consistent with the degree of inflammation. Mice lacking Fc gamma RIII showed almost no PG depletion, whereas in Fc gamma RII(-/-) mice, PG depletion was increased 3-7-fold in various cartilage areas. Initiation of erosive cartilage destruction, as reflected by MMP-mediated VDIPEN expression, was reduced in Fc gamma RIII(-/-) and Fc gamma RI(-/-) mice, directing the two different critical steps of cellular influx and subsequent activation. These aspects were enhanced in Fc gamma RII(-/-) mice. In Fc gamma RI(-/-) and Fc gamma RIII(-/-) mice, VDIPEN expression was 90-99% lower, whereas in Fc gamma RII(-/-) mice, VDIPEN expression was increased 4-fold. Chondrocyte death was reduced in Fc gamma RIII(-/-) mice (68% lower) and enhanced in Fc gamma RII(-/-) mice (6-12-fold higher). Progression of arthritis and erosion of the cartilage surface were markedly elevated in Fc gamma RII(-/-) arthritic joints. CONCLUSION: During ICA, Fc gamma RIII is the dominant activating receptor mediating joint inflammation, whereas both Fc gamma RI and Fc gamma RIII are involved in cartilage destruction. Fc gamma RII inhibits both joint inflammation and severe cartilage destruction during ICA.

Animals↗
PubMed2003

Inhibition of cartilage degradation: a combined tissue engineering and gene therapy approach.

OBJECTIVE: To determine if tissue-engineered cartilage can be protected from cytokine-induced degradation using a gene therapy approach. METHODS: Chemical and pantropic retroviral gene transfer methodologies were compared for their ability to introduce a luciferase reporter gene into adult bovine cartilage chondrocytes grown in monolayer. Pantropic retrovirus was then used to transduce these cells with human tissue inhibitor of metalloproteinases 1 (TIMP-1), and the stability of expression in monolayer or pellet culture was monitored for 6 weeks. Untransduced and TIMP-1-transduced cells were also used to tissue engineer 3-dimensional cartilage constructs that were then challenged with interleukin-1 (IL-1) for 4 weeks. Conditioned media and residual cartilage were collected for analysis of matrix components, including type II collagen and proteoglycans, and for TIMP-1 production and matrix metalloproteinase (MMP) activity. RESULTS: Chemical transfection of adult bovine chondrocytes gave rise to short-lived reporter expression that was virtually undetectable after 4 weeks of culture. In contrast, pantropic retroviral transduction gave rise to stable expression that persisted at a high level for at least 6 weeks. Pantropic transduction of the cells with TIMP-1 gave rise to similar long-term expression, both in monolayer and pellet cultures. TIMP-1-transduced tissue-engineered cartilage also retained TIMP-1 expression for an additional 4 weeks of culture in the presence of IL-1. Compared with control samples, TIMP-1-transgenic cartilage resisted the catabolic effects of IL-1, with MMP activity reduced to basal levels and a decreased loss of type II collagen. CONCLUSION: Pantropic retroviral transduction permits long-term expression of potentially therapeutic transgenes in adult tissue-engineered cartilage. While TIMP-1 transduction could be used to prevent collagen breakdown, alternative transgenes may be necessary to protect cartilage proteoglycans.

Animals↗
PubMed2003

Longitudinal analysis of cartilage atrophy in the knees of patients with spinal cord injury.

OBJECTIVE: A previous cross-sectional study indicated that the morphology of patellar and tibial cartilage is subject to change after spinal cord injury (SCI). The aim of this study was to perform a longitudinal analysis of cartilage atrophy in all knee compartments, including the femoral condyles, in SCI patients over 12 months. METHODS: The right knees of 9 patients with complete, traumatic SCI were examined shortly after the injury (mean +/- SD 9 +/- 4 weeks) and at 6 and 12 months postinjury. Three-dimensional morphology of the patellar, tibial, and femoral cartilage (mean and maximum thickness, volume, and surface area) was determined from coronal and transversal magnetic resonance images (fat-suppressed gradient-echo sequences) using validated postprocessing techniques. RESULTS: The mean thickness of knee joint cartilage decreased significantly during the first 6 months after injury (range 5-7%; P < 0.05). The mean change at 12 months was 9% in the patella, 11% in the medial tibia, 11% in the medial femoral condyle, 13% in the lateral tibia, and 10% in the lateral femoral condyle (P < 0.05 for all compartments). CONCLUSION: This is the first report of a longitudinal analysis of cartilage atrophy in patients with SCI. These data show that human cartilage atrophies in the absence of normal joint loading and movement after SCI, with a rate of change that is higher than that observed in osteoarthritis (OA). A potential clinical implication is that cartilage thinning after SCI may affect the stress distribution in the joint and render it vulnerable to OA. Future studies should focus on whether specific exercise protocols and rehabilitation programs can prevent cartilage thinning.

Adolescent↗
PubMedDate not supplied

Electron microscopic studies of the cartilage-pannus junction in rheumatoid arthritis.

The junction between pannus and cartilage was examined in the rheumatoid joint. Three types of cartilage-pannus junction were observed. In one, proliferating small blood vessels, surrounded by highly cellular infiltrates, penetrated deeply into the cartilage. Degeneration of the cartilage was observed around the cellular accumulations. In the second, phagocytic and fibroblastic cells invaded the cartilage. In the third, fibrous pannus overlay the cartilage. Lysis of cartilage by infiltrating cells appeared to be a major cause of cartilage erosion in rheumatoid arthritis.

Acid Phosphatase↗
PubMed1977

Surface ultrastructure of rheumatoid articular cartilage.

Six rheumatoid articular cartilage specimens, which appeared grossly normal and were shown to be free of pannus when examined under the light microscope, were examined electron microscopically. For comparison, normal-appearing cartilage specimens from 2 patients with meniscus injury and 2 with degenerative joint disease (DJD) were also examined. In all cases the normal-appearing joint surface of rheumatoid cartilage was abnormal. Amorphous-appearing material was present to a depth varying between 6 and 25 micron. Some of this material had the appearance of fibrin deposited at the cartilage surface, but much appeared to represent breakdown products of the cartilage matrix, i.e. degraded collagen and proteoglycan. DJD cartilage did not show similar changes. The findings suggest that the surface of rheumatoid articular cartilage, even when grossly normal in appearance, is degraded by enzymes either present in the synovial fluid or released by polymorphonuclear cells in close contact with the cartilage surface.

Adult↗
PubMed1980

Marked suppression by salicylate of the augmented proteoglycan synthesis in osteoarthritic cartilage.

In osteoarthritis a net increase in proteoglycan synthesis has been noted until the disease is far advanced and presumably reflects an attempt by the chondrocyte to repair the defect in the cartilage matrix. Because salicylates are the agents most commonly employed in treatment of osteoarthritis and because we recently showed that 10(-3) M sodium salicylate (i.e., approximately 20 mg%) suppresses proteoglycan synthesis in normal canine knee cartilage in vitro, we have studied the effects of this compound on osteoarthritis knee cartilage from dogs whose anterior cruciate ligament had been transected 9 weeks previously. The data indicated that the augmented synthesis of glycosaminoglycans in the degenerating cartilage was suppressed to a much greater degree by 10(-3) M sodium salicylate than the lower level of glycosaminoglycan synthesis in control cartilage from the contralateral knee of the same animal. Uptake of 14C-acetylsalicylic acid was increased about 35% in osteoarthritic cartilage, suggesting that the drug permeated it more readily than normal cartilage. The salicylate-induced suppression of proteoglycan synthesis in the osteoarthritic cartilage was not accompanied by reversal of the defect in proteoglycan aggregation or by improvement in the (presumed) defect in proteoglycan-collagen interaction in the matrix, as reflected by the abnormally high proportion of 35S-proteoglycans present in the culture medium.

Animals↗
PubMed1984

Effects of salicylate and indomethacin on glycosaminoglycan and prostaglandin E2 synthesis in intact canine knee cartilage ex vivo.

The effects of salicylate and indomethacin on glycosaminoglycan synthesis by intact articular cartilage were examined ex vivo. Distal femora of normal dogs were transected at the diaphysis and incubated in medium containing sodium salicylate or indomethacin and 35SO4. Uronic acid contents of habitually loaded and habitually unloaded regions of the condyles averaged 4.2% and 3.1% of the tissue dry weight, respectively. Salicylate had no effect on glycosaminoglycan synthesis in cartilage from loaded sites but suppressed synthesis by 18% (P less than 0.01) in cartilage from unloaded sites, while indomethacin had no effect on glycosaminoglycan synthesis in either region. Evidence that the drugs indeed diffused into the cartilage, even when no effects on glycosaminoglycan metabolism were noted, was provided by measurements of prostaglandin E2. At the concentrations used, both indomethacin and salicylate markedly reduced prostaglandin E2 synthesis by the cartilage. In studies with 14C-acetylsalicylic acid or 14C-indomethacin, the concentration of each drug in cartilage was calculated to be about 3 logs lower than that in the culture medium. Furthermore, drug concentrations in cartilage from loaded zones were consistently lower than those in cartilage from unloaded sites.

Animals↗
PubMed1985

Proteoglycan depletion, rather than fibrillation, determines the effects of salicylate and indomethacin on osteoarthritic cartilage.

The effects of salicylate and indomethacin on glycosaminoglycan (GAG) synthesis by atrophic and osteoarthritic (OA) canine cartilage were examined in vitro by transecting distal femora at the metaphysis and incubating the knuckle, with its overlying cap of articular cartilage, in medium containing sodium salicylate or indomethacin, and 35SO4. Atrophic cartilage had an intact articular surface, but its uronic acid content averaged 65% of the control level, and GAG synthesis was decreased to 50% of control values. Both salicylate and indomethacin decreased net GAG synthesis in the atrophic cartilage by an additional 10%. OA cartilage showed surface disruption, a uronic acid content 49% of the control value, and a 49% increase in net GAG synthesis. Salicylate and indomethacin profoundly decreased GAG synthesis in the OA cartilage. However, GAG synthesis and uronic acid content of cartilage which had been lacerated in vitro immediately prior to culture (to stimulate fibrillation) were normal and not affected by either drug. The data emphasize the importance of matrix proteoglycan content in protecting the chondrocyte from the suppressive effects of salicylate and indomethacin on GAG metabolism, and suggest that the lower proteoglycan content of OA cartilage may be more important than fibrillation in rendering it vulnerable to the metabolic effects of these drugs.

Animals↗
PubMed1985

Cartilage degradation by neutral proteoglycanases in experimental osteoarthritis. Suppression by steroids.

In this study, we sought to determine the role of neutral proteases in cartilage matrix proteoglycan degradation, which occurs during the early stages of experimental osteoarthritis. The anterior cruciate ligament was transected in the right knees of 33 dogs. Their left knees served as sham operated controls. The animals were killed 2, 4, 8, and 12 weeks after surgery. Six dogs were treated with oral prednisone and then killed 4 weeks after surgery. Cartilage specimens from medial and lateral tibial plateaus were analyzed for DNA, proteoglycan content, and neutral proteoglycan degrading activity. No significant differences in cartilage DNA and proteoglycan content were observed among the dogs that had surgery, the controls, and the prednisone-treated animals. Total neutral metalloproteoglycan-degrading enzyme (NMPE) activity, determined by direct tissue assay, was significantly higher at all time points in osteoarthritic cartilage than in control cartilage. The active form of NMPE was significantly higher in osteoarthritic cartilage than in control cartilage at 2, 4, and 8 weeks in lateral plateaus and at 2 and 4 weeks in medial plateaus. Treatment for 4 weeks with prednisone (0.20-0.25 mg/kg/day) blocked the increased NMPE activity in osteoarthritic cartilage. The increase in the total and active neutral proteoglycanases supports the hypothesis that these enzymes are involved in early osteoarthritis. The synthesis of NMPE appears to be controlled by stimulating factors released by the synovium.

Animals↗
PubMed1986

Alterations in a cartilage matrix glycoprotein in canine osteoarthritis.

A number of biochemical abnormalities have been described in osteoarthritic (OA) cartilage, but little study has been devoted to changes in the noncollagenous, nonproteoglycan proteins of cartilage in this condition. Using a canine model of OA produced by transection of the anterior cruciate ligament of the knee, we have demonstrated that distinct alterations occur in a 550,000-dalton cartilage matrix glycoprotein in OA canine cartilage. This protein is a major protein constituent of normal articular cartilage. Fragments which are immunologically cross-reactive with the 550,000-dalton protein were more abundant in OA cartilage than in normal articular cartilage. Immunofluorescence studies revealed that staining with specific antiserum to the protein was absent in OA cartilage. This was the only noncollagenous, nonproteoglycan protein noted to undergo significant changes in this model of OA.

Animals↗
PubMed1991

In vivo effects of interleukin-1 on articular cartilage. Prolongation of proteoglycan metabolic disturbances in old mice.

We investigated the effects of intraarticular injections of interleukin-1 alpha (IL-1 alpha) into the knee joints of young (3-month-old) and old (18-month-old) C57Bl/10 mice. In this in vivo study, 35S-sulfate incorporation and release were used to compare the effects of IL-1 on patellar cartilage proteoglycan metabolism. IL-1-induced stimulation of proteoglycan degradation was confined to the first 24 hours after injection in both young and old animals, and was only slightly lower in old cartilage than in young. In old patellar cartilage, IL-1-induced suppression of proteoglycan synthesis appeared to be more prolonged. Also, the amount of time needed to restore the cartilage matrix, characterized by proteoglycan synthesis above normal levels, was longer in old animals. Histologic analysis confirmed the retarded recovery in the cartilage of old mice. Autoradiography showed that the chondrocytes of the medial side of the femorotibial area were most vulnerable to IL-1-induced suppression of proteoglycan synthesis, especially the medial tibial plateau. As with the patellar cartilage, IL-1-induced suppression of proteoglycan synthesis in this area of articular cartilage was more prolonged in old animals. Our data indicated that the impact of IL-1 on articular cartilage is higher in old mice and that, consistent with certain loci found to be at risk in experimental osteoarthritis, there are sites at which IL-1 is more likely to act.

Aging↗
PubMed1991

Phospholipase A2 is a major component of the salt-extractable pool of matrix proteins in adult human articular cartilage.

Adult human articular cartilage contains a component with an apparent molecular weight of 16 kd, which is extractable with high ionic strength buffers. This protein, which, in addition to lysozyme, is one of the most prominent components in salt extracts of adult cartilage, is not detectable in cartilage from newborns. We performed N-terminal sequence analysis to identify the protein. The amino acid sequence obtained for the first 20 residues was identical to that reported for phospholipase A2 (PLA2) from human placenta and human synovial cells. The extractable PLA2 was found to be active. The lack of PLA2 in salt extracts from newborn cartilage observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis was confirmed by the very low levels of PLA2 activity detectable in these preparations. PLA2 was clearly present in cartilage extracts from an 18-year-old subject and a 19-year-old subject, suggesting that its accumulation begins at some stage during the adolescent growth period. The enzyme does not appear to be released from cartilage matrix under normal physiologic conditions, and it is possible that the accumulation of PLA2 in maturing cartilage is a result of the decreased matrix turnover associated with the termination of skeletal growth. Whether PLA2 is active in the cartilage matrix, its precise localization, and its effects on the resident chondrocytes remain to be determined.

Adolescent↗
PubMed1993

Release of cartilage macromolecules into the synovial fluid in patients with acute and prolonged phases of reactive arthritis.

OBJECTIVE: Extensive changes in articular cartilage metabolism occur during the acute phase of reactive arthritis, as indicated by altered release of cartilage macromolecules into synovial fluid (SF) demonstrated immunochemically. Nevertheless, permanent cartilage lesions are rare in this disease. To monitor specific events during the evolution of reactive arthritis, we investigated the content of cartilage macromolecules in sequentially obtained SF samples from 22 patients. METHODS: Two groups of proteoglycan epitopes, the glycosaminoglycan-rich region of aggrecan (referred to as proteoglycan) and its hyaluronan-binding region (HABr), as well as one matrix protein, cartilage oligomeric matrix protein (COMP), were quantified by immunoassay. RESULTS: SF proteoglycan concentrations, which were initially elevated, decreased significantly with prolonged arthritis, whereas COMP levels changed less markedly and levels of HABr remained stable. There was a positive correlation between SF and serum concentrations of COMP in samples obtained during the early phase of the disease. CONCLUSION: Cartilage involvement in reactive arthritis is transient, in contrast to findings in rheumatoid arthritis. Reactive arthritis should therefore be a suitable model for studies of repair processes in cartilage, which will facilitate understanding of the pathophysiology of cartilage involvement in arthritis.

Adult↗
PubMed1993

Degradation of human articular cartilage by neutrophils in synovial fluid.

OBJECTIVE: To determine whether surface-adherent immunoglobulins are capable of mediating synovial fluid (SF) neutrophil degradation of proteoglycan and collagen in intact, normal human articular cartilage, and to define the respective roles of neutrophil serine proteases and metalloproteases in degrading these cartilage constituents. METHODS: Pellet explants of normal human articular cartilage pretreated with bovine serum albumin (BSA) or IgG were incubated with polymorphonuclear cells suspended in SF (PMN-SF), or with supernatants derived from neutrophils stimulated with surface-associated IgG. Proteoglycan degradation was measured by assaying release of 35S-proteoglycan fragments from cartilage explants prelabeled with 35S-sulfate. Collagen degradation was measured by assaying hydroxyproline content in the PMN-SF preparations or neutrophil supernatants following their incubation with unlabeled explants. RESULTS: Significant release of both 35S fragments and hydroxyproline was noted following incubation of PMN-SF with IgG-treated pellets, compared with pellets treated with BSA. IgG preparations derived from pooled normal serum or rheumatoid arthritis SF were equally efficacious in mediating PMN degradation of cartilage collagens. Explant release of 35S fragments during incubation with PMN supernatant was completely inhibited when serine proteases were inactivated by diisopropyl fluorophosphate (DFP); however, release of 35S fragments was enhanced when metalloprotease activity was present in the supernatant. Release of hydroxyproline during incubation of explants with PMN supernatant was comparable in the presence of DFP or EDTA, but was markedly enhanced when both serine and metalloprotease activity were present in the supernatant. CONCLUSION: Neutrophils in SF are capable of degrading both proteoglycans and collagens in intact human articular cartilage. Degradation of these cartilage constituents is facilitated by immunoglobulins adherent to the cartilage surface and by the synergistic action of PMN serine and metalloproteases released during activation of neutrophils with surface-associated immunoglobulin.

Arthritis, Rheumatoid↗
PubMed1994

A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice.

OBJECTIVE: A new animal model was used to study the interaction between rheumatoid synovial cells and cartilage and to explore the cellular basis of rheumatoid joint destruction. METHODS: Fresh synovial tissue derived from patients with rheumatoid arthritis was implanted with normal human cartilage into SCID mice, either subcutaneously or under the renal capsule, for up to 304 days. The implants were analyzed by light and electron microscopy, as well as by immunohistochemistry and in situ hybridization. RESULTS: Human synovial tissue and cartilage implanted in SCID mice are maintained by the animals for up to 304 days. After 35 days, focal erosions occur at the site of attachment of synovial lining cells to the cartilage. After 105 days, a pannus-like formation, consisting of proliferating synovial fibroblast-like cells invading the cartilage, is observed. The fibroblast nature of these cells was supported by observation of only focal expression of the macrophage markers CD14 and CD68. Cells at the immediate site of cartilage destruction express messenger RNA for cathepsin L, whereas cathepsin D messenger RNA was detected in subsynovial regions away from the site of destruction. The human origin of the tissue involved in cartilage destruction was demonstrated using monoclonal antibodies to HLA-ABC and human type IV collagen. CONCLUSION: The present approach introduces a novel in vivo model of rheumatoid arthritis for the study of the molecular and cellular mechanisms of rheumatoid joint destruction at sites of synovial attachment to cartilage. In this model, the SCID mouse acts as a useful host for studying the properties of rheumatoid synovium in the absence of circulating human blood components.

Animals↗