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Elastic system components have been described in the pressure-bearing tendon of the bullfrog, Rana catesbeiana, as a result of histochemical tests and transmission and scanning electron microscopy. The tension region was shown to possess microfibril bundles, some of which exhibited central deposits of amorphous material. The use of ANS-butanol plus fluorescence microscopy enormously facilitated the identification of elastic system components in both tension and compression regions of the frog tendon. The compression region exhibited pre-elastic and mature elastic fibers, which were shown to be associated with the surface of the convoluted collagen bundles. Thin fibrils were observed in the compression region after ANS treatment. The visceral paratenon had an increased number of elastic fibers located between the collagen bundles and close to the cells. Congo red plus polarization microscopy failed to impart birefringence to the elastic fibers, but they could be identified by their intense staining and isotropic appearance against the bright background of birefringent collagen fibers. SEM demonstrated the three-dimensional aspects of the elastic fibers. They are composed of fibrils of a sinuous nature. The use of ruthenium red in the fixative allowed for the observation of an intimate association of proteoglycan granules with the microfibril bundles. The elastic components identified in the pressure-bearing tendon are assumed to be important for the tissue supramolecular organization, especially in the maintenance of the convoluted state of the collagen fibers in the compression region and their crimp morphology in the tension region. The elastic system must also play an important role in the restoration of the resting shape of the tendon after the deformation achieved during mechanical stimulation.
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PMID:The elastic system of a pressure-bearing tendon of the bullfrog Rana catesbeiana. 764 34

Interleukin 1 (IL-1) is a cytokine which induces cartilage proteoglycan (PG) depletion by inhibiting PG synthesis and increasing PG breakdown. Insulin-like growth factor I (IGF-I), in contrast, is known to promote matrix formation. We examined the effects of both mediators in a bovine tissue culture model. IL-1 dose-dependently inhibited PG formation of articular cartilage [half-maximal effect (EC50) at 4 ng/ml], while PG synthesis was increased by IGF-I (EC50 = 15 ng/ml). After inhibition of PG formation with IL-1 for 2 days and subsequent removal of free IL-1, addition of IGF-I dose-dependently accelerated restoration of the original rate of synthesis with a half-maximal effect at 20 ng/ml and a maximal effect at 50 ng/ml. The IGF-I concentration required to elicit a half-maximal effect on cartilage PG synthesis remained constant in the absence or presence of IL-1. We therefore conclude that inhibition of cartilage PG synthesis by IL-1 is not effected by damage to the IGF receptor. Synovial fluid (SF) of 40 patients with rheumatoid arthritis (RA) was found to contain 64 +/- 6 ng IGF-I/ml (mean +/- SEM). The reported effects of IGF-I in vitro therefore occurred at concentrations comparable to those present in joints in vivo. IL-1 beta was detectable (> 0.5 pg/ml) in 38 of 40 RA-SF samples (mean 28 +/- 6 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-like growth factor I accelerates recovery of articular cartilage proteoglycan synthesis in culture after inhibition by interleukin 1. 769 49

A number of human and mouse macrophage and fibroblast cell lines were examined for their ability to degrade cartilage proteoglycan in an attempt to establish a cell culture model of cartilage degradation. The mouse transformed macrophage cell line J774A.1 alone or in combination with the mouse transformed fibroblast cell line 10ME HD A.5R.1 were the only cell lines capable of extensively degradating cartilage proteoglycan. Incubation of the macrophage cell line J774A.1 on heat-killed cartilage disks resulted in the release of 36% +/- 8 (mean +/- SEM, n = 5) of the radiolabeled cartilage proteoglycan. The fibroblast cell line 10ME HD A.5R.1 alone did not degrade cartilage. However, cocultures of J774A.1 macrophages and 10ME HD A.5R.1 fibroblasts incubated on cartilage discs resulted in the release of 69% +/- 6 (mean +/- SEM, n = 5) of radiolabeled proteoglycan. There was little degradation of cartilage by macrophage/fibroblast cocultures during the first 3 days of culture. Cartilage degradation increased with each subsequent day in culture from 7% +/- 2 on day 4 to 68% +/- 3 (n = 3) by day 7. Supernatants from the macrophage/fibroblast cocultures were incubated with cartilage discs in the presence of general class-specific proteinase inhibitors. The metalloproteinase inhibitors 1,10 phenanthroline, EDTA, and recombinant tissue inhibitor of metalloproteinase were the only inhibitors that significantly blocked cartilage degradation by coculture supernatant. The cartilage degrading metalloproteinase in the macrophage/fibroblast coculture supernatant eluted as a broad peak on Sephacryl S-200HR with an estimated molecular mass between 22 and 55 kDa. These studies suggest that the macrophage/fibroblast coculture model of cartilage degradation may be a useful experimental system for the study of metalloproteinase-mediated connective tissue degradation.
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PMID:Cartilage degradation by cocultures of transformed macrophage and fibroblast cell lines. A model of metalloproteinase-mediated connective tissue degradation. 843 25

In this study we determined the efficiency of magnetization transfer magnetic resonance imaging (MT-MRI) to differentiate native and enzymatically degraded cartilage, using bovine sesamoid bones from the metacarpophalangeal joint as a model system. Gradual proteoglycan (PG) depletion was achieved by increasing incubation periods with testicular hyaluronidase. For native cartilage a Ms/Mo ratio of 0.303 +/- 0.09 (mean +/- SEM) was measured. Biochemically determined PG diminution up to 50% correlated strongly (r = 0.953) with changes in the Ms/Mo ratio. Further PG loss is not reflected in an equally drastic Ms/Mo increase, whereas subsequent treatment of PG-depleted cartilage samples with collagenase led to an additional rise in the Ms/Mo ratio. Proteoglycan depletion and the beginning destruction of the collagen structure were also assessed histochemically. Our study confirms that collagen contributes to the baseline MT effect observed in articular cartilage. However, the changes in the MT ratio in gradually PG-depleted cartilage with a largely intact collagen network indicate that PG contributes to the MT effect as well. Therefore MT-MRI might become a sensitive technique for the monitoring of subtle degradational changes in articular cartilage, the still inaccessible process in osteoarthritis.
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PMID:Can magnetization transfer magnetic resonance imaging follow proteoglycan depletion in articular cartilage? 921 83

Dunkin Hartley guinea pigs develop spontaneous, age-related osteoarthritis (OA) of the knee and other joints. Histologic changes are observed beginning at 3 months of age. Disease severity increases with age, and at 18 months moderate to severe OA is observed. A study was undertaken to assess the morphologic and biochemical changes of 22-month-old animals, and to compare them with values in 2-month-old guinea pigs. Biochemical indices characteristic of OA, from tibial cartilage, indicated an increase in proteoglycan content from 233 +/- 2 micrograms/mg (mean +/- SEM) at 2 months of age to 365 +/- 6 micrograms/mg at 22 months. Collagen concentration in cartilage decreased from 364 +/- 2 micrograms/mg at 2 months to 223 +/- 3 micrograms/mg at 22 months. Proteoglycan fragments found in synovial fluid measured 4.6 +/- 1 micrograms/ml at 2 months and increased to 37 +/- 2 micrograms/ml at 22 months. Radiographic changes observed at 22 months included marginal osteophytes of the tibia and femur, sclerosis of the subchondral bone of the tibial plateau, femoral condyle cysts, and calcification of the collateral ligaments. Histologic evaluation revealed severe OA, with a Mankin score of 10.7 +/- 0.5 in 22-month-old animals. In contrast, 2-month-old animals had no histologic or radiographically detectable lesions. The results of the study reported here indicate that the lesions observed in this model are similar to those of human OA. Spontaneous development of OA in guinea pigs is amenable to the study of the pathogenesis of OA and to the evaluation of potential disease-modifying agents.
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PMID:Spontaneous osteoarthritis in Dunkin Hartley guinea pigs: histologic, radiologic, and biochemical changes. 943 95

To determine whether systemic administration of methotrexate (MTX) can prevent joint destruction in experimental osteoarthrosis (OA) in rabbits, the disorder was induced unilaterally in the knee joints of 40 rabbits by partial medial meniscectomy and sectioning of the medial collateral and both cruciate ligaments. A sham operation (arthrotomy only) was performed in another four animals. Effects on the cartilage of the femoral condyles were studied after 6 and 12 weeks. Twelve weeks after induction, femoral and tibial osteophyte formation was demonstrated on radiographs in all cases. Marked cartilage damage was found histologically (median Mankin score 10 vs 1 for non-operated controls; P < 0.05, Wilcoxon test). Cartilage proteoglycan (GAG) content (dye binding assay) was reduced in operated joints [63 +/- 8 (mean +/- SEM) vs 75 +/- 6 micrograms chondroitin sulfate/mg cartilage wet weight], and the leukocyte count in the joints was elevated (226 +/- 14 vs 7 +/- 3 leukocytes per microliter joint aspirate after injection of 0.5 ml saline solution; both P < 0.05, Wilcoxon test). The rate of GAG synthesis was unchanged (ex vivo labelling with 35S-sulfate). Treatment with MTX (30 mg x kg body weight-1 x week-1 i.m., starting 12 h postoperatively) reduced cartilage damage (median Mankin score 8 vs 10 for placebo, P < 0.05, Mann-Whitney U-test), but had no significant effect on the other parameters tested. No significant MTX effects were observed on cartilage from nonoperated joints. Our data indicate that MTX may have a limited therapeutic effect in experimental OA in the rabbit.
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PMID:The effects of high-dose methotrexate on the development of cartilage lesions in a lapine model of osteoarthrosis. 958 Dec 58

We previously reported that mutation of the transforming growth factor-beta3 (TGF-beta3) gene caused cleft palate in homozygous null (-/-) mice. TGF-beta3 is normally expressed in the medial edge epithelial (MEE) cells of the palatal shelf. In the present study, we investigated the mechanisms by which TGF-beta3 deletions caused cleft palate in 129 x CF-1 mice. For organ culture, palatal shelves were dissected from embryonic day 13.5 (E13.5) mouse embryos. Palatal shelves were placed singly or in pairs on Millipore filters and cultured in DMEM/F12 medium. Shelves were placed in homologous (+/+ vs +/+, -/- vs -/-, +/- vs +/-) or heterologous (+/+ vs -/-, +/- vs -/-, +/+ vs +/-) paired combinations and examined by macroscopy and histology. Pairs of -/- and -/- shelves failed to fuse over 72 hours of culture whereas pairs of +/+ (wild-type) and +/+ or +/- (heterozygote) and +/-, as well as +/+ and -/- shelves, fused within the first 48 hour period. Histological examination of the fused +/+ and +/+ shelves showed complete disappearance of the midline epithelial seam whereas -/- and +/+ shelves still had some seam remnants. In order to investigate the ability of TGF-beta family members to rescue the fusion between -/- and -/- palatal shelves in vitro, either recombinant human (rh) TGF-beta1, porcine (p) TGF-beta2, rh TGF-beta3, rh activin, or p inhibin was added to the medium in different concentrations at specific times and for various periods during the culture. In untreated organ culture -/- palate pairs completely failed to fuse, treatment with TGF-beta3 induced complete palatal fusion, TGF-beta1 or TGF-beta2 near normal fusion, but activin and inhibin had no effect. We investigated ultrastructural features of the surface of the MEE cells using SEM to compare TGF-beta3-null embryos (E 12. 5-E 16.5) with +/+ and +/- embryos in vivo and in vitro. Up to E13.5 and after E15.5, structures resembling short rods were observed in both +/+ and -/- embryos. Just before fusion, at E14.5, a lot of filopodia-like structures appeared on the surface of the MEE cells in +/+ embryos, however, none were observed in -/- embryos, either in vivo or in vitro. With TEM these filopodia are coated with material resembling proteoglycan. Interestingly, addition of TGF-beta3 to the culture medium which caused fusion between the -/- palatal shelves also induced the appearance of these filopodia on their MEE surfaces. TGF-beta1 and TGF-beta2 also induced filopodia on the -/- MEE but to a lesser extent than TGF-beta3 and additionally induced lamellipodia on their cell surfaces. These results suggest that TGF-beta3 may regulate palatal fusion by inducing filopodia on the outer cell membrane of the palatal medial edge epithelia prior to shelf contact. Exogenous recombinant TGF-beta3 can rescue fusion in -/- palatal shelves by inducing such filopodia, illustrating that the effects of TGF-beta3 are transduced by cell surface receptors which raises interesting potential therapeutic strategies to prevent and treat embryonic cleft palate.
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PMID:Pathogenesis of cleft palate in TGF-beta3 knockout mice. 1043 15

Spinal motor neurons possess reticular coats of extracellular matrix proteoglycans on their somata and proximal dendrites. In order to define the anatomical background of the network, spatial relationships of the perineuronal proteoglycans with synaptic boutons and astrocyte processes were analyzed in rat motor neurons by TEM after histochemical detection of the substances with cationic iron colloid, and by SEM after exposure of the cytoarchitecture with NaOH maceration. Narrow intercellular channels filled with proteoglycan were found to extend along the surface of the neurons to form a homogeneous network of a mesh size of about 1 microm. The system of perineuronal channels consisted of two parts: a primary intervaricose net which meandered among synaptic boutons on the surface of the motor neuron, and secondary subvaricose nets which irrigated interfaces between larger boutons and the neuron. No elements in the perineuronal cytoarchitecture coincided with the meshwork of proteoglycan, indicating the involvement of postsynaptic factors in the distribution of the substance. Thin astrocyte processes surrounding the neurons formed a distinct network with heterogeneous meshes corresponding to boutons of various sizes. The perineuronal glial nets extended their surface area in contact with the intervaricose nets of proteoglycan by complex cellular interdigitations. The subvaricose nets of proteoglycan compartmentalized multiple synapses on large boutons, suggesting an involvement in the division of the synapses during development.
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PMID:Three-dimensional microanatomy of perineuronal proteoglycan nets enveloping motor neurons in the rat spinal cord. 1045 28

Adaptive changes in the menisci and adjacent posterior capsule were documented within anterior cruciate ligament-deficient knee (stifle) joints in the goat model. These physical changes in the menisci and capsule developed over time and were associated with reduction in the initial (time zero) abnormal anterior tibial translation following transection of the anterior cruciate ligament. At 50 N of applied force, the normal goat knee joint has a total anterior-posterior translation of 0.6+/-0.1 mm (+/- SEM) at 45 degrees of flexion and 0.3+/-0.1 mm at 90 degrees. The translation immediately after transection (time zero) with 50 N of force was 8.2+/-0.5 mm at 45 degrees and 4.9+/-0.9 mm at 90 degrees. Within 8 months after transection and at 50 N of force, the treated knees had reduced translation values of 5.3+/-0.6 mm at 45 degrees of flexion and 2.9+/-0.5 mm at 90 degrees, or 35 (p<0.001) and 40% reductions, respectively, compared with the values at time zero. Magnetic resonance images of the ligament-deficient stifle joints, as well as gross measurements and image analysis after dissection, consistently demonstrated increases in cross-sectional area and volume of the menisci compared with the contralateral controls. These secondary changes were most pronounced in the posterior portion of the medial menisci, and histologic evaluation demonstrated hypercellularity with the accumulation of poorly organized collagen, reduced safranin O staining (proteoglycan matrix synthesis), a thickened capsule and capsule attachment, and increased vascularity at the meniscal capsule interface.
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PMID:Reduced anterior tibial translation associated with adaptive changes in the anterior cruciate ligament-deficient joint: goat model. 1063 46

Decorin is an extracellular matrix (ECM) proteoglycan that may modify vascular smooth muscle cell (SMC) function by altering the response to growth factors and the accumulation of ECM proteins during vascular injury. To investigate these possibilities in vivo, decorin was overexpressed at the site of arterial injury by cell-mediated gene transfer. Fischer rat SMCs were transduced in vitro with a retroviral construct that contained the bovine decorin gene and were subsequently seeded into injured rat carotid arteries. A species-specific antibody to bovine decorin and polymerase chain reaction primers were used to detect bovine decorin and distinguish it from endogenous rat decorin. Immunohistochemical and Northern analyses of rat carotid arteries revealed only low levels of rat decorin expression up to 8 weeks after balloon injury. However, after cell-mediated transfer of bovine decorin, strong expression of bovine decorin was verified by immunohistochemistry and reverse transcriptase-polymerase chain reaction. Four weeks after injury, the intimal area in vessels seeded with bovine decorin-overexpressing SMCs was significantly reduced by 35+/-4% (mean+/-SEM, n=9; P<0.01). Decorin overexpression also induced a higher intimal nuclear density and decreased volume of ECM. Specifically, immunostaining for versican and fibronectin was markedly reduced. In contrast, immunostaining for collagen type I was increased, and electron microscopy confirmed that collagen accumulation was altered. Bromodeoxyuridine labeling indicated that intimal SMC proliferation was not affected by the expression of bovine decorin. In summary, we demonstrate that gene transfer of the ECM proteoglycan, decorin, into the injured arterial wall reduces intimal ECM volume and alters the composition of the ECM.
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PMID:Local expression of bovine decorin by cell-mediated gene transfer reduces neointimal formation after balloon injury in rats. 1074 4


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