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PubMed1990

Proteoglycan alterations following immobilization and remobilization in the articular cartilage of young canine knee (stifle) joint.

The distribution of proteoglycans (PGs) at 11 sites on the knee (stifle joint) cartilage of young female beagle dogs was studied following cast immobilization for 11 weeks in 90 degrees flexion and after a subsequent remobilization for 15 weeks. Immobilization induced a reduction in PG uronic acid at all sites (mean of -38%), but the greatest depletion (-64%) occurred at the anterior and posterior extremes of the femoral condyles, i.e., at locations where the immobilized cartilage lost contact to the opposing cartilage. Following remobilization, the content of uronic acid remained lower than in the age-matched controls (-18% on average), particularly at the minimum contact sites most affected by immobilization (-33%). The chondroitin-6-sulfate to chondroitin-4-sulfate ratio was reduced by immobilization in most locations (average of -14%) and returned to control values after remobilization. There was no consistent change in the percentage of aggregating PGs observed in Sephacryl S-1000 gel filtration after immobilization or remobilization. However, following remobilization, the aggregating PGs showed an enhanced proportion of the slower mobility band in agarose gel electrophoresis, indicative of a larger monomer size. In the contralateral, load-bearing knee joint, both the uronic acid content and PG monomer type distribution were identical to those observed in the experimental joint, suggesting that the state reached after the remobilization period was due to factor(s) influencing both sides. The results suggest that contact forces between articulating surfaces are required to maintain normal PG content and that the control mechanism works locally at each cartilage site. Restriction of joint mobility and loading in young animals is concluded to cause persistent changes in cartilage matrix. Furthermore, the use of the contralateral joint as the sole control in this kind of studies, although experimentally convenient, seems not to be appropriate.

Animals↗
PubMed1993

Immunolocalization of selected cytokines and proteases in canine articular cartilage after transarticular loading.

Cytokines and proteases are thought to play a role in the destruction of cartilage and the development of osteoarthritis. The purpose of this study was to document chronological involvement of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), stromelysin (MMP-3), fibronectin, and alteration in the chondroitin sulphate sulfation pattern. Canine patellae underwent a closed-joint impact to induce the development of osteoarthritis. The animals were killed at 2, 12, 24, and 52 weeks. The patellar damage included cracks in the superficial zone of cartilage and the zone of the calcified cartilage-bone interface, vertical step-off fractures in the zone of calcified cartilage, and loss of proteoglycan around the cracks in the deep and superficial zones of cartilage. With avidin-biotin immunohistochemistry, these specimens were stained with antibodies to IL-1 beta, TNF-alpha, MMP-3, fibronectin, and altered proteoglycan sulfate with the monoclonal antibody 3-B-3. Three of the four specimens obtained at 2 weeks demonstrated a strong cellular and weak matrix staining pattern for IL-1 beta, TNF-alpha, MMP-3, and fibronectin around the cracks in the superficial and transitional zones of cartilage. No consistent staining pattern was noted in the cracks in the deep zone. None of the specimens obtained at 12, 24, or 52 weeks stained for these antibodies. No staining for the abnormal sulfation with the 3-B-3 antibody was evident in any specimen. The specimens obtained at 52 weeks showed healing of the step-off fractures and a filling-in of the proteoglycan loss. This model probably reflects the short-term cartilaginous changes in the patella after trauma; thus, only transient elevations in the cytokines and proteases were evident.

Animals↗
PubMed1994

Electric field stimulation can increase protein synthesis in articular cartilage explants.

It has been hypothesized that the electric fields associated with the dynamic loading of cartilage may affect its growth, remodeling, and biosynthesis. While the application of exogenous fields has been shown to modulate cartilage biosynthesis, it is not known what range of field magnitudes and frequencies can alter biosynthesis and how they relate to the magnitudes and frequencies of endogenous fields. Such information is necessary to understand and identify mechanisms by which fields may act on cartilage metabolism. In this study, incorporation of 35S-methionine was used as a marker for electric field-induced changes in chondrocyte protein synthesis in disks of cartilage from the femoropatellar groove of 1 to 2-week-old calves. The cartilage was stimulated sinusoidally at 1, 10, 100, 10(3), and 10(4) Hz with current densities of 10-30 mA/cm2. Incorporation was assessed in control disks maintained in the absence of applied current at 37, 41, and 43 degrees C. The possibility that applied currents would induce synthesis of the same stress proteins that are caused by heating or other mechanisms was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and examination of gel fluorographs. Total radiolabel incorporation in cartilage that had been stimulated relative to incorporation in the controls increased with current density magnitudes greater than 10 mA/cm2. The increase was greatest at 100 Hz and 1 kHz, and it depended on the position on the joint surface from which the cartilage samples were taken. Together, these results suggest that endogenous electric fields could affect cartilage biosynthesis. Stress proteins were not induced at any current density when the electrodes were electrically connected but chemically isolated from the media by agarose bridges. Stress proteins were observed for disks incubated at temperatures greater than 39 degrees C (no field) and when the stimulating platinum electrodes were in direct contact with the media bathing the cartilage disks. Therefore, the increase in incorporation of 35S-methionine due to applied fields with the use of chemically isolated electrodes did not appear to be associated with stress response.

Animals↗
PubMed1996

Swelling and fibronectin accumulation in articular cartilage explants after cyclical impact.

The objective of this study was to determine if repeated impact could damage living cartilage and lead to osteoarthritis-like changes in its biology. Canine cartilage explants were subjected to impacts of as much as 50 MPa once every 5 seconds for 30 minutes. On each impact cycle, the loading rate was 100 MPa/sec to the assigned peak stress, which was held for 1 second. After impact testing, the cartilage was kept in defined culture for as long as 10 days. Radiosulfate incorporation in the region that received direct impact varied with load 0-4 hours after impact, but it did not vary with load at 20-24 hours after impact. Even so, most explants were visibly damaged by 20 or 50 MPa, and there was subtle evidence of damage from impacts of 5 or 10 MPa. For example, ion-induced swelling in 0.01 M NaCl was increased, suggesting that the physical integrity of the matrix was reduced relative to controls. Self-diffusion of water, measured by proton magnetic resonance imaging was also increased in the deeper zones of the explant, consistent with changes in structure at the molecular level. Ten days after impact, the water content and the fibronectin content of the loaded region of the explant were both increased. In combination, these osteoarthritis-like changes suggested that the physical strength of normal cartilage limits its ability to withstand cyclical impact.

Animals↗
PubMed2006

Healing of articular cartilage defects. An experimental study of vascular and minimal vascular microenvironment.

The repair potential in a chondral defect with (treatment A) or without access to bone marrow elements (treatment B) at the basis of the defect sealed by a rim-sutured periosteal flap was studied using adult New Zealand rabbits (22 weeks) as an experimental model. At sacrifice, macroscopical changes, synovial fluid contents, degree of filling, thickness of the cartilage rim, and the subchondral bone were evaluated. Histomorphometric measurements of extent of filling (mainly fibrous tissue) of the defect at 36 weeks postoperatively, showed 50% filling in treatment A compared with 33% in treatment B (p = 0.011). A difference in height of the cartilage rim between the experimental groups and sham-control was measured ( p = 0.005). Cartilage degeneration was observed at the cartilage rim of the original defect, and included loss of chondrocytes and disruption of surface continuity in both experimental groups. In addition, treatment A resulted in a significantly increased thickness of the subchondral bone in the defect in comparison to treatment B at 2 weeks and at 36 weeks (p = 0.021). The increased thickness of the subchondral bone may be of concern for the bone marrow stimulation techniques regarding the long-term outcome.

Animals↗
PubMed2006

Development of partial thickness articular cartilage injury in an ovine model.

The purpose of this study was to create a controlled partial thickness cartilage lesion in a sheep model, and to provide a foundation to study the natural history of the progression of this lesion. Twenty-eight sheep divided into four groups (1, 12, 24, and 52 weeks, n=7/group) were used in this study. In one stifle, a mechanical tool was used to create a 200 microm partial thickness lesion (1.5x1.5 cm2) on the medial femoral condyle via arthroscopy. Joint fluid was drawn presurgery and after euthanasia for analysis of collage II 3/4 C (long) (C2C). After euthanasia, the condyle was analyzed by gross appearance, confocal laser microscopy (CLM) for cell viability, scanning electronic microscopy (SEM) for surface roughness, Artscan for cartilage stiffness, and histology for cartilage morphology. The gross appearance of the treated area appeared rough, soft, and swollen compared to untreated control over time. CLM demonstrated that the depth of cell death increased to 590 microm at 52 weeks after surgery. SEM demonstrated that the treated area became more irregular over time. Stiffness of the treated area was significantly less than control by 12 weeks after surgery. Histologic analysis demonstrated that the 12, 24, and 52 week groups had significantly poorer histologic scores than the 1 week group. Joint fluid analysis demonstrated that the treatment group at 1 week had significant higher levels of C2C than the pretreatment baseline data. The results of this study demonstrated that partial thickness injury of cartilage continued to propagate and degenerate over time in this sheep model. Options for the prevention or treatment of this lesion may be tested using this model in the future.

Animals↗
PubMed1989

Effect of Nd:YAG laser energy on articular cartilage healing in the dog.

The effect of low dose neodymium:yttrium aluminum garnet (Nd:YAG) laser therapy on cartilage healing was studied. Partial- and full-thickness cartilage defects were surgically created in the femoral condyles of 20 adult dogs. The cartilage defects in one limb of each dog were exposed to 30 J of Nd:YAG laser energy. The dogs were euthanatized 1 week (n = 6), 1 month (n = 7), and 6 months (n = 7) after surgery. Plastic-embedded, undecalcified histologic sections of each cartilage defect were examined for evidence of cartilage healing. Special stains were used to determine the type of repair tissue present, and morphometric measurements of repair tissue were made. No effect of Nd:YAG laser therapy on cartilage healing was noted.

Animals↗
PubMed2003

Optimization of diffusion measurements using Cramer-Rao lower bound theory and its application to articular cartilage.

A novel approach to optimized diffusion measurements by minimizing the Cramer-Rao lower bound (CRLB) with respect to the b-values used for diffusion measurement was investigated. The applicability of the CRLB to these measurements is shown by the close agreement between the CRLB prediction and the actual precision obtained from experimental results. Where studies using a propagation-of-errors approach have restricted the optimization of the diffusion measurement to two b-values and to specific diffusion coefficient values, the CRLB approach sets no bounds on the number of b-values and is applicable to any system. The optimal number of b-values depends on the ratio of the maximum and minimum diffusion coefficients in the sample (the D(ratio)) and on the number of acquisitions. For a D(ratio) above 6.8 the optimal number of b-values increases to three; at a D(ratio) of 21.8 it increases to four. The optimized sampling schemes for ADC measurements in a variety of representative tissues found in the human body are given. For cartilage the optimal five-point acquisition scheme requires one measurement at a b-value of 0 and four at 1036 sec mm(-2), whereas brain requires one at 0, three at 660, and one at 1987 sec mm(-2).

Animals↗
PubMed2004

T2 and T1rho MRI in articular cartilage systems.

T2 and T1rho have potential to nondestructively detect cartilage degeneration. However, reports in the literature regarding their diagnostic interpretation are conflicting. In this study, T2 and T1rho were measured at 8.5 T in several systems: 1) Molecular suspensions of collagen and GAG (pure concentration effects): T2 and T1rho demonstrated an exponential decrease with increasing [collagen] and [GAG], with [collagen] dominating. T2 varied from 90 to 35 ms and T1rho from 125 to 55 ms in the range of 15-20% [collagen], indicating that hydration may be a more important contributor to these parameters than previously appreciated. 2) Macromolecules in an unoriented matrix (young bovine cartilage): In collagen matrices (trypsinized cartilage) T2 and T1rho values were consistent with the expected [collagen], suggesting that the matrix per se does not dominate relaxation effects. Collagen/GAG matrices (native cartilage) had 13% lower T2 and 17% lower T1rho than collagen matrices, consistent with their higher macromolecular concentration. Complex matrix degradation (interleukin-1 treatment) showed lower T2 and unchanged T1rho relative to native tissue, consistent with competing effects of concentration and molecular-level changes. In addition, the heterogeneous GAG profile in these samples was not reflected in T2 or T1rho. 3) Macromolecules in an oriented matrix (mature human tissue): An oriented collagen matrix (GAG-depleted human cartilage) showed T2 and T(1rho) variation with depth consistent with 16-21% [collagen] and/or fibril orientation (magic angle effects) seen on polarized light microscopy, suggesting that both hydration and structure comprise important factors. In other human cartilage regions, T2 and T1rho abnormalities were observed unrelated to GAG or collagen orientation differences, demonstrating that hydration and/or molecular-level changes are important. Overall, these studies illustrate that T2 and T1rho are sensitive to biologically meaningful changes in cartilage. However, contrary to some previous reports, they are not specific to any one inherent tissue parameter.

Animals↗
PubMed2006

Collagen dynamics in articular cartilage under osmotic pressure.

Cartilage is a complex biological tissue consisting of collagen, proteoglycans and water. The structure and molecular mobility of the collagen component of cartilage were studied by (13)C solid-state NMR spectroscopy as a function of hydration. The hydration level of cartilage was adjusted between fully hydrated ( approximately 80 wt% H(2)O) and highly dehydrated ( approximately 30 wt% H(2)O) using the osmotic stress technique. Thus, the conditions of mechanical load could be simulated and the response of the tissue macromolecules to mechanical stress is reported. From the NMR measurements, the following results were obtained. (i) Measurements of motionally averaged dipolar (1)H-(13)C couplings were carried out to study the segmental mobility in cartilage collagen at full hydration. Backbone segments undergo fast motions with amplitudes of approximately 35 degrees whereas the collagen side-chains are somewhat more mobile with amplitudes between 40 and 50 degrees . In spite of the high water content of cartilage, collagen remains essentially rigid. (ii) No chemical shift changes were observed in (13)C cross-polarization magic angle spinning spectra of cartilage tissue at varying hydration indicating that the collagen structure was not altered by application of high osmotic stress. (iii) The (1)H-(13)C dipolar coupling values detected for collagen signals respond to dehydration. The dipolar coupling values gradually increase upon cartilage dehydration, reaching rigid limit values at approximately 30 wt% H(2)O. This indicates that collagen is essentially dehydrated in cartilage tissue under very high mechanical load, which provides insights into the elastic properties of cartilage collagen, although the mechanical pressures applied here exceed the physiological limit.

Animals↗
PubMed2006

Sodium and T1rho MRI for molecular and diagnostic imaging of articular cartilage.

In this article, both sodium magnetic resonance (MR) and T1rho relaxation mapping aimed at measuring molecular changes in cartilage for the diagnostic imaging of osteoarthritis are reviewed. First, an introduction to structure of cartilage, its degeneration in osteoarthritis (OA) and an outline of diagnostic imaging methods in quantifying molecular changes and early diagnostic aspects of cartilage degeneration are described. The sodium MRI section begins with a brief overview of the theory of sodium NMR of biological tissues and is followed by a section on multiple quantum filters that can be used to quantify both bi-exponential relaxation and residual quadrupolar interaction. Specifically, (i) the rationale behind the use of sodium MRI in quantifying proteoglycan (PG) changes, (ii) validation studies using biochemical assays, (iii) studies on human OA specimens, (iv) results on animal models and (v) clinical imaging protocols are reviewed. Results demonstrating the feasibility of quantifying PG in OA patients and comparison with that in healthy subjects are also presented. The section concludes with the discussion of advantages and potential issues with sodium MRI and the impact of new technological advancements (e.g. ultra-high field scanners and parallel imaging methods). In the theory section on T1rho, a brief description of (i) principles of measuring T1rho relaxation, (ii) pulse sequences for computing T1rho relaxation maps, (iii) issues regarding radio frequency power deposition, (iv) mechanisms that contribute to T1rho in biological tissues and (v) effects of exchange and dipolar interaction on T1rho dispersion are discussed. Correlation of T1rho relaxation rate with macromolecular content and biomechanical properties in cartilage specimens subjected to trypsin and cytokine-induced glycosaminoglycan depletion and validation against biochemical assay and histopathology are presented. Experimental T1rho data from osteoarthritic specimens, animal models, healthy human subjects and as well from osteoarthritic patients are provided. The current status of T1rho relaxation mapping of cartilage and future directions is also discussed.

Animals↗
PubMed1993

Evidence for a glycosaminoglycan chain on a portion of articular cartilage fibronectins.

Fibronectin heterogeneity is, in part, the result of post-translational modifications. In these experiments, cartilage fibronectins were purified by anion exchange chromatography, followed by gelatin affinity chromatography or immunoprecipitation, and, finally, sodium dodecyl sulfate--polyacrylamide gel electrophoresis (NaDodSO4 PAGE). A substantial, although variable, portion of the fibronectins from canine and equine cartilages of all ages required salt concentrations from 0.2 to 1.0 M for elution from DEAE-cellulose. This was in contrast to plasma fibronectin which eluted with 0.1 M NaCl, but these results were consistent with observations made on human cartilage by Brown and Jones (1990 J. Rheumatol. 17, 65-72). When cartilage explants were incubated with Na2 35SO4=, the cartilage fibronectins were sulfated and the fibronectins which eluted with high salt contained from 5- to 50-fold more radiosulfate than the fibronectins which eluted with 0.1 M NaCl. A fraction of the 35SO4= which copurified with the cartilage fibronectin and comigrated with it in NaDodSO4-PAGE could be removed by digestion with chondroitinase ABC. This suggested that a percentage of cartilage fibronectins are covalently linked to a chondroitin sulfate or dermatan sulfate chain and thus might also appropriately be called proteoglycans. Alternatively, there is a proteoglycan which binds so tightly to fibronectin that separation is not achieved even in the presence of urea, sodium dodecyl sulfate, and mercaptoethanol.

Animals↗
PubMed1994

Transforming growth factor-beta stimulates retinoic acid-induced proteoglycan depletion in intact articular cartilage.

Cartilage-bearing sesamoid bones from the metacarpophalangeal joints of adult cows were cultured with retinoic acid for 1 week and allowed to recover in control medium for another 2 weeks. Retinoic acid decreased the proteoglycan synthesis of the cartilage to 33% of control values, and induced 26% loss of proteoglycans from the matrix. During recovery, the synthesis of proteoglycans returned to the control level but their content remained reduced. Transforming growth factor-beta (TGF-beta 1, 5 ng/ml) was added to the culture medium to stimulate the recovery. However, TGF-beta depressed the synthesis of proteoglycans and increased their loss to 61%. Only the large aggregating species, aggrecan, was lost from the matrix. The half-life of proteoglycans synthesized during recovery in control medium was 12.7 days, which was reduced to 8.7 days by TGF-beta. The proteoglycan half-life in control cartilage cultured without retinoic acid or TGF-beta was 33.8 days. Neither retinoic acid nor TGF-beta-induced changes in the hyaluronate content of the tissue. Aggrecans and small proteoglycans synthesized in the presence of TGF-beta were larger than those in controls. The synthesis of the small proteoglycans was stimulated 4.5-fold by TGF-beta, and their content was increased. The results show that TGF-beta can stimulate depletion of aggrecan in retinoic acid-treated cartilage. This indicates a catabolic function of TGF-beta in cartilage remodeling.

Aggrecans↗
PubMed1995

Accumulation of fibronectin in articular cartilage explants cultured with TGF beta 1 and fucoidan.

Fibronectin is a glycoprotein involved in cell matrix interactions. In osteoarthritis, fibronectin levels in the lesion cartilage are elevated up to 20-fold above control levels. In these experiments, explants of disease-free cartilage cultured in the presence of a combination of TGF beta 1 and the sulfated fucopolysaccharide, fucoidan, accumulated fibronectin at levels comparable to those found in osteoarthritic lesions. TGF beta 1 increased fibronectin synthesis, most of which was released to the medium. The addition of fucoidan favored retention of the newly synthesized fibronectin within the matrix. The fibronectin which accumulated as a result of these treatments was similar to the fibronectin in normal and osteoarthritic cartilage with respect to the ED-B+ alternative splice form. No change in the proteoglycan content of the cartilage explants with elevated fibronectin levels was detected.

Animals↗
PubMed1995

Insulin-like growth factor-I and its complexes in normal human articular cartilage: studies of partition and diffusion.

Insulin-like growth factor-I (IGF-I) plays a major role in cartilage homeostasis. Our objective was to study the penetration of IGF-I, both alone and bound to serum proteins, into the different zones of normal human cartilage using radioactively labeled IGF-I. The uptake of free IGF-I was higher than that predicted on the basis of excluded volume calculations and showed concentration dependence: we attributed this to reversible binding of the hormone to the tissue. Since the extent of binding was much higher than that calculated for binding to cell receptors, we concluded that IGF-I binds to matrix components. The kinetics of desorption of IGF-I from cartilage confirmed our conclusions regarding binding. The degree of uptake of IGF-I protein complexes prepared by labeling human serum with [125I]IGF-I showed that such complexes are largely excluded from normal cartilage and that the amounts present in the tissue are too low to affect proteoglycan metabolism.

Absorption↗
PubMed1996

Activation and inhibition of endogenous matrix metalloproteinases in articular cartilage: effects on composition and biophysical properties.

Bovine cartilage explants were cultured with 1 mM 4-aminophenylmercuric acetate (APMA) to activate endogenous matrix metalloproteinases (MMPs) and changes in biochemical, biomechanical, and physicochemical properties were assessed. Additionally, graded levels of either rhTIMP-1 (recombinant human tissue inhibitor of metalloproteinases-1) or L-696-418 (a synthetic metalloproteinase inhibitor) were used to inhibit degradation induced by APMA. Treatment with APMA resulted in as much as 80% loss in tissue GAG content, a greater than threefold increase in denatured type II collagen as determined by the presence of CB11B epitope, and complete loss of biosynthetic activity after 3 days in culture. Physicochemical studies revealed that APMA treatment resulted in a significant increase in tissue swelling response, consistent with damage to the collagen network. Activation of MMPs by APMA also resulted in > 80% decrease in equilibrium modulus, dynamic stiffness, and streaming potential and > 50% decrease in electrokinetic coupling coefficient. The addition of 4 microM, 400 nM, and 40 nM TIMP inhibited PG loss by 95, 50, and 20%, respectively, and all doses effectively inhibited swelling response. The addition of 4 microM and 400 nM L-696-418 inhibited PG loss by 95% while 40 nM L-696-418 inhibited PG loss by 60%, and all doses effectively inhibited swelling response. The inhibition of APMA-induced GAG loss by 4 microM TIMP was accompanied by maintenance of streaming potential, electrokinetic coupling coefficient, dynamic stiffness, and equilibrium modulus.

Animals↗
PubMed2001

Effects of ceramide on aggrecanase activity in rabbit articular cartilage.

Ceramide participates in signal transduction of IL-1 and TNF, two cytokines likely involved in cartilage degradation in osteoarthritis. We previously showed that ceramide stimulates proteoglycan degradation, mRNA expression of matrix metalloproteinase (MMP)-1, -3, and -13, and pro-MMP-3 production in rabbit cartilage. Since aggrecan, the main cartilage proteoglycan, can be cleaved by metalloproteinases both of MMP and aggrecanase type, the aim of this study was to determine if ceramide stimulates aggrecanase action and, if that is the case, in which measure aggrecanase mediates the degradative effect of ceramide. To this end, antibodies were used against the C terminal aggrecan neoepitopes generated by aggrecanases (NITEGE(373)) and MMPs (DIPEN(341)). Ceramide C(2) at 10(-5) to 10(-4) M dose-dependently increased NITEGE signal, without changing that of DIPEN, in cultured explants of rabbit cartilage. The effects of 10(-4) M C(2) on NITEGE signal and proteoglycan degradation were similarly antagonized by the metalloproteinase inhibitor batimastat, with return to the basal level at 10(-6) M. These results show that, similarly to IL-1 and TNF, ceramide-induced aggrecan degradation is mainly due to aggrecanases. That no increase of MMP activity was detected, despite stimulation of MMP expression, was probably due to lack of proenzyme conversion to mature form, since addition of a MMP activator to C(2)-treated cartilage increased both DIPEN signal and proteoglycan degradation. These findings support the hypothesis that cytokine-induced ceramide could play a mediatory role in situations of increased degradation of cartilage matrix.

Aggrecans↗