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PubMed1995

Increased proteoglycan synthesis in cartilage in experimental canine osteoarthritis does not reflect a permanent change in chondrocyte phenotype.

OBJECTIVE: To determine whether chondrocytes in early experimental osteoarthritic (OA) cartilage continue to show increased synthesis and turnover of proteoglycans (PGs) during explant culture. A comparison was also made between the responsiveness of experimental OA and control cartilage to interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) after 1 day and 3 days in culture. METHODS: OA was induced in mature animals by sectioning of the anterior cruciate ligament followed by 3 months of normal exercise. PG synthesis in the articular cartilage was determined by measuring 35S-sulfate incorporation during explant culture over 1-3 days. Inhibition of PG synthesis was also determined with various concentrations of IL-1 beta and TNF alpha after 1 and 3 days in culture. PGs extracted from the articular cartilage over 1-3 days in culture were examined by agarose-polyacrylamide gel electrophoresis. RESULTS: Up to 24 hours after excision from the joint, PG synthesis was higher in experimental OA cartilage than in control cartilage. It was also less sensitive to inhibition by TNF alpha. These differences were no longer detected after 48-72 hours in culture. There were no changes in the relative proportions of aggrecan and decorin/biglycan extracted from and synthesized by control and experimental OA cartilage over the 3 days in culture. CONCLUSION: Previous results indicated that PG synthesis and turnover in articular cartilage was increased for many months after induction of experimental OA. Our present results show that the enhanced rate of PG synthesis and turnover were evident in freshly explanted tissue, but the differences were lost over 3 days in culture. A decreased responsiveness to TNF alpha was also lost. The hypermetabolic activity of experimental OA chondrocytes was thus reversible and not a permanent change in chondrocyte phenotype.

Aggrecans↗

PubMed1996

The superficial layer of human articular cartilage is more susceptible to interleukin-1-induced damage than the deeper layers.

OBJECTIVE: To compare the responses of chondrocytes from superficial and deep layers of normal human articular cartilage to interleukin-1 (IL-1) and IL-1 receptor antagonist protein (IRAP), and to evaluate the binding sites for IL-1 on these cells. METHODS: Cartilage and chondrocytes from superficial and deeper layers of human femoral condyles were cultured with and without IL-1 in the presence and absence of IRAP. The effect of these agents on 35S- proteoglycan synthesis and catabolism and production of stromelysin and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by biochemical and immunologic assays. Receptor binding was evaluated using 125I-labeled IL-1. RESULTS: IL-1 induced more severe inhibition of proteoglycan synthesis and a lower ratio of secreted TIMP-l:stromelysin in chondrocytes from superficial cartilage than those from deeper cartilage. IRAP blocked responses to IL-1 more effectively in chondrocytes from deep cartilage than those from superficial cartilage. Chondrocytes from the articular surface showed approximately twice the number of high-affinity b!nding sites for IL-1 as did cells from deep cartilage. CONCLUSION: Chondrocytes from the surface of articular cartilage show a greater vulnerability to the harmful effects of IL-1 and are less responsive to the potential therapeutic effects of IRAP than cells in the deeper layers of the tissue.

Adolescent↗

PubMed1996

Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-10 and interleukin-4.

OBJECTIVE: Inflammation-induced articular cartilage degradation is a major problem in rheumatoid arthritis (RA). Type 1 T cell activity (characterized by interferon-gamma/interleukin-2 [IL-2] production), and consequently, the production of the proinflammatory cytokines IL-1 and tumor necrosis factor alpha (TNF alpha), have been reported to play a major role in cartilage damage. IL-10 and IL-4, both produced by type 2 T cells, are cytokines with the capacity to down-regulate proinflammatory responses. The present study was undertaken to investigate the way in which these cytokines affect activated mononuclear cells (MNC) of RA patients in relation to human articular cartilage degradation in vitro. METHODS: MNC from synovial fluid and peripheral blood of RA patients were stimulated with bacterial antigen and treated with IL-10 and/or IL-4. Bacterial antigen is known to activate type 1 T cells and to induce proinflammatory IL-1/TNF alpha-dependent cartilage damage. Cytokine production and effects of conditioned media, as well as effects of IL-10 and IL-4 on proteoglycan (PG) turnover (as a measure for cartilage damage), were determined. RESULTS: IL-10 and IL-4 inhibited proinflammatory cytokine production of stimulated RA MNC and completely reversed inhibition of cartilage PG synthesis induced by these stimulated RA MNC. IL-10 was more potent than IL-4 in this respect, and the combination of IL-10 and IL-4 had an additive effect. In addition, IL-10 directly stimulated cartilage PG synthesis. CONCLUSION: IL-10 reverses the cartilage degradation induced by antigen-stimulated MNC, and IL-4 has an additive effect on this process. Furthermore, IL-10 has a direct stimulatory effect on PG synthesis, and IL-4, as a growth factor for type 2 T cells, can reduce the ratio of type 1 to type 2 T cell activity. These results provide evidence in favor of the use of a combination of the two cytokines in the treatment of RA.

Adult↗

PubMed1997

Degradation of type II collagen, but not proteoglycan, correlates with matrix metalloproteinase activity in cartilage explant cultures.

OBJECTIVE: To determine the contribution of certain matrix metalloproteinases (MMPs) to the degradation of proteoglycan and type II collagen in cartilage. METHODS: Bovine nasal and articular cartilage explants were cultured with recombinant human interleukin-1 alpha (IL-1 alpha) for up to 4 weeks. Release of proteoglycan and type II collagen into the medium was determined by colorimetric assay and immunoassay, respectively. The activity of MMPs in the medium was assayed using a quenched fluorescent substrate, as well as with a collagen fibril assay, by zymography, and in Western immunoblots. In some experiments, the effects of specific MMP inhibitors on type II collagen degradation were studied. RESULTS: In cultures of nasal cartilage with IL-1 alpha, almost all the proteoglycan was released within the first week, whereas there was no detectable release of type II collagen for the first 2 weeks of culture. A rapid period of almost complete dissolution of the collagen occurred in the third or fourth week. MMP activity measured using a quenched fluorescent substrate was negligible during the first 2 weeks of culture but was substantially increased in the third week of culture, at the time of collagen degradation. Similarly, there was a large increase in collagenolytic activity (by collagen fibril assay) and gelatinolytic activity (by zymography) during the third week of culture. Articular cartilage cultured with IL-1 alpha lost proteoglycan progressively during the 4-week period; however, there was no loss of type II collagen from the matrix in that time and no significant increase in MMP activity. The loss of type II collagen from nasal cartilage stimulated with IL-1 alpha was inhibited by BB87, an inhibitor of both collagenases and gelatinases, and by BB3003, a selective inhibitor of gelatinase A. In Western immunoblots, procollagenase and active interstitial collagenase could be readily detected in nasal cartilage cultures. Some procollagenase 3 and active collagenase 3 was also shown to be present. CONCLUSION: MMP activity correlates with degradation of type II collagen, but not proteoglycan, in cartilage cultures. Interstitial collagenase, collagenase 3, and gelatinases are all likely to contribute to cleavage and removal of collagen from the cartilage matrix. The proteinase(s) responsible for aggrecan breakdown remains unclear.

Animals↗

PubMed2004

The genetic contribution to muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis: a sibpair study.

OBJECTIVE: To estimate the heritability of muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis (ROA), and to assess whether heritability of the knee structural components is independent of ROA. METHODS: A sibpair design was utilized. Sagittal T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine cartilage volume and bone size. Standing semiflexed radiographs of the same knee were obtained to assess the presence of ROA. Knee pain was assessed by questionnaire and muscle strength by dynamometry. Heritability was estimated using the genetic analysis program SOLAR. RESULTS: A total of 128 subjects (61 men, 67 women; mean age 45 years) from 51 families representing 115 sibpairs were studied. Lower limb muscle strength had high heritability (42%; P = 0.02), as did knee pain (44%; P = 0.07). Heritability estimates for cartilage volume were 65% for medial tibial cartilage, 77% for lateral tibial cartilage, and 84% for patellar cartilage, and heritability estimates for bone size were 85% for medial tibial bone area, 57% for lateral tibial bone area, and 70% for patella bone volume (all P < or = 0.004). For ROA, heritability was 61% for presence (with a large standard error) (P = 0.16) and 61% for severity (P = 0.02). The estimates for tibial bone areas were the only ones markedly reduced after adjustment for body size, while all estimates with the exception of knee pain were independent of ROA. Cartilage and, to a lesser extent, bone sites investigated by MRI were largely under independent genetic control, with a lesser shared genetic component. CONCLUSION: With the exception of prevalent ROA, all knee modalities assessed had high heritability, most likely reflecting a strong genetic component. Cartilage volume, bone size, and muscle strength all have the potential to be studied in quantitative trait linkage analyses, but their exact relevance with regard to OA remains uncertain at this time.

Adult↗

PubMed2004

Lectin-like oxidized low-density lipoprotein receptor 1 mediates matrix metalloproteinase 3 synthesis enhanced by oxidized low-density lipoprotein in rheumatoid arthritis cartilage.

OBJECTIVE: To investigate for the presence of oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor 1 (LOX-1) in cartilage specimens from rheumatoid arthritis (RA) joints and to determine whether the interaction of ox-LDL with LOX-1 can induce matrix metalloproteinase 3 (MMP-3) in articular cartilage explant culture. METHODS: Human articular cartilage specimens obtained from patients with RA, osteoarthritis (OA), and femoral neck fractures were examined for LOX-1 and ox-LDL by confocal fluorescence microscopy. The association between ox-LDL and LOX-1 was evaluated by immunofluorescence analysis. Articular cartilage specimens from patients with femoral neck fractures were incubated with ox-LDL, with or without preincubation with neutralizing anti-LOX-1 antibody. MMP-3 synthesis by chondrocytes in explant cartilage was evaluated by immunofluorescence, and protein secretion into conditioned medium was monitored by immunoblotting and enzyme-linked immunosorbent assay. RESULTS: The majority of the RA chondrocytes stained positively with both anti-LOX-1 and anti-ox-LDL antibodies; however, no positive cells were found in OA and normal cartilage specimens. Anti-LOX-1 antibody suppressed the binding of DiI-labeled ox-LDL to chondrocytes in explant culture, suggesting that the interaction was mediated by LOX-1. In contrast to native LDL, ox-LDL induced MMP-3 synthesis by articular chondrocytes in association with the induction of LOX-1, which resulted in enhanced secretion of MMP-3 into the culture medium. Anti-LOX-1 antibody reversed ox-LDL-stimulated MMP-3 synthesis to control levels. CONCLUSION: Ox-LDL, principally mediated by LOX-1, enhanced MMP-3 production in articular chondrocytes. Increased accumulation of ox-LDL with elevated expression of LOX-1 in RA cartilage indicates a specific role of the receptor-ligand interaction in cartilage pathology in RA.

Antibodies↗

PubMed2005

Effect of inhibition of matrix metalloproteinases on cartilage loss in vitro and in a guinea pig model of osteoarthritis.

OBJECTIVE: To study the effects of a matrix metalloproteinase (MMP) inhibitor (S-34219) on osteoarthritis (OA) cartilage cultures and in the meniscectomized guinea pig model of OA. METHODS: The inhibitory activity of S-34219 on MMPs and aggrecanase was studied by fluorimetry and immunoassay, respectively. The effects of S-34219 on proteoglycan and collagen degradation were studied in cultures of rabbit and human cartilage. Medial meniscectomy was performed on 29 Hartley male guinea pigs, and these animals were randomly allocated to 1 of 3 groups: a control meniscectomized group (MNXc) receiving the vehicle, or a meniscectomized group receiving either 10 mg/kg or 20 mg/kg S-34219, administered twice per day by oral gavage for 12 weeks from day 1 after surgery. An additional group comprised sham-operated animals. Tibial cartilage from the operated left knee was processed for histologic assessment of OA lesions. RESULTS: The 50% inhibitory concentration (IC(50)) of S-34219 on MMPs 1, 2, 3, 8, 9, and 13 was 55, 0.1, 0.5, 0.1, 0.03, and 0.2 nM, respectively; the IC(50) on aggrecanase 1 was 190 nM. In cultured rabbit cartilage, 100 nM S-34219 strongly inhibited MMP-dependent degradation of collagen and proteoglycans. A concentration 100 times higher was needed to inhibit aggrecanase-dependent degradation. In cultures of human OA cartilage, 100 nM S-34219 inhibited spontaneous type II collagen degradation by 66% and proteoglycan degradation by only 22%. For in vivo studies, treated groups were compared with the MNXc group and the results, expressed as the percentage variation versus MNXc, were as follows: in the 10 and 20 mg/kg groups, a significant decrease (P < 0.05) in global histologic score (-12% and -14%, respectively) was observed, and this was associated with a significant increase (P < 0.05) in cartilage thickness (+19% and +18%, respectively). Neither dose level changed the proteoglycan content. CONCLUSION: In both treated animal groups, S-34219 significantly prevented the loss of cartilage thickness, probably by inhibiting collagen breakdown that normally leads to the erosion of fibrillated superficial areas. The absence of a protective effect on glycosaminoglycan loss, both in vitro and in vivo, suggests that aggrecanases may have an important role in cartilage loss. This study reinforces the relevance of these models for testing chondroprotective drugs, and the potential role of dual inhibitors of collagenase and aggrecanase as disease-modifying drugs in the management of OA.

Animals↗

PubMed2005

Factors associated with hip cartilage volume measured by magnetic resonance imaging: the Tasmanian Older Adult Cohort Study.

OBJECTIVE: To compare associations between anthropometric and lifestyle factors and femoral head cartilage volume/thickness and radiographic features of osteoarthritis (OA) and to provide evidence of construct validity for magnetic resonance imaging (MRI) assessment of femoral cartilage volume and thickness. METHODS: We studied a cross-sectional sample of 151 randomly selected subjects (79 men, 72 women; mean age 63 years) from the Tasmanian Older Adult Cohort Study. A sagittal T1-weighted fat-suppression MRI scan of the right hip was performed to determine femoral head cartilage volume, cartilage thickness, and size. An anteroposterior radiograph of the pelvis with weight bearing was performed and scored for radiographic evidence of OA in the right hip. Other factors measured were height, weight, leg strength, serum vitamin D levels, and bone mineral density. RESULTS: Hip cartilage volume was significantly associated with female sex, body mass index, and femoral head size, whereas hip cartilage thickness was significantly associated only with the size of the femoral head. Only female sex was significantly associated with the total radiographic OA score and the joint space narrowing (JSN) score, but not the osteophyte score. Radiographic JSN of the hip, especially axial JSN (but not osteophytes), was significantly correlated with hip cartilage volume and thickness. CONCLUSION: Femoral head cartilage volume and thickness have modest but significant construct validity when correlated with radiographic findings. Furthermore, the generally stronger associations with volume compared with radiographic OA suggest that MRI may be superior at identifying risk factors for hip OA.

Aged↗

PubMed2005

Accuracy and precision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) of articular cartilage represents a powerful tool in osteoarthritis (OA) research, but has so far been confined to a field strength of 1.5T. The aim of this study was to evaluate the precision of quantitative MRI assessments of human cartilage morphology at 3.0T and to correlate the measurements at 3.0T with validated measurements at 1.5T. METHODS: MR images of the knee of 15 participants with OA and 15 healthy control subjects were acquired using Siemens 1.5T and 3.0T scanners. Double oblique coronal scans were obtained at 1.5T with a 1.5-mm partition thickness, at 3.0T with a 1.5-mm partition thickness, and at 3.0T with a 1.0-mm partition thickness. Cartilage volume, thickness, and surface area of the femorotibial cartilage plates were quantified using proprietary software. RESULTS: For 1.5-mm partition thickness at 1.5T, the precision error was 3.0% and 2.6% for cartilage volume and cartilage thickness, respectively. The error was smaller for a 1.5-mm partition thickness at 3.0T (2.6% and 2.5%) and still smaller for a 1.0-mm partition thickness at 3.0T (2.1% and 2.0%). Correlation coefficients between values obtained at 3.0T and 1.5T were high (r > or = 0.96), with no significant deviation between the two field strengths. CONCLUSION: Quantitative MRI measurement of cartilage morphology at 3.0T (partition thickness 1 mm) was found to be accurate and tended to be more reproducible than at 1.5T (partition thickness 1.5 mm). Imaging at 3.0T may therefore provide superior ability to detect changes in cartilage status over time and to determine responses to treatment with structure-modifying drugs.

Aged↗

PubMed2006

The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis.

OBJECTIVE: To explore the role of meniscal tears and meniscal malposition as risk factors for subsequent cartilage loss in subjects with symptomatic osteoarthritis (OA). METHODS: Study subjects were patients with symptomatic knee OA from the Boston Osteoarthritis of the Knee Study. Baseline assessments included knee magnetic resonance imaging (MRI) with followup MRI at 15 and 30 months. Cartilage and meniscal damage were scored on MRI in the medial and lateral tibiofemoral joints using the semiquantitative whole-organ magnetic resonance imaging score. Tibiofemoral cartilage was scored on MR images of all 5 plates of each tibiofemoral joint, and the meniscal position was measured using eFilm Workstation software. A proportional odds logistic regression model with generalized estimating equations was used to assess the effect of each predictor (meniscal position factor and meniscal damage as dichotomous predictors in each model) on cartilage loss in each of the 5 plates within a compartment. Models were adjusted for age, body mass index (BMI), tibial width, and sex. RESULTS: We assessed 257 subjects whose mean +/- SD age was 66.6 +/- 9.2 years and BMI was 31.5 +/- 5.7 kg/m2; 42% of subjects were female, and 77% of knees had a Kellgren/Lawrence radiographic severity grade > or = 2. In the medial tibiofemoral joint, each measure of meniscal malposition was associated with an increased risk of cartilage loss. There was also a strong association between meniscal damage and cartilage loss. Since meniscal coverage and meniscal height diminished with subluxation, less coverage and reduced height also increased the risk of cartilage loss. CONCLUSION: This study highlights the importance of an intact and functioning meniscus in patients with symptomatic knee OA, since the findings demonstrate that loss of this function has important consequences for cartilage loss.

Aged↗

PubMed2006

Increase in bone marrow lesions associated with cartilage loss: a longitudinal magnetic resonance imaging study of knee osteoarthritis.

OBJECTIVE: Although bone marrow lesions (BMLs) are powerful predictors of joint space loss as visualized on radiographs, the natural history of these lesions, their relationship to cartilage loss, and the association between change in these lesions and cartilage loss are unknown. These questions were tested using longitudinal magnetic resonance imaging (MRI) data in a natural history study of symptomatic knee osteoarthritis (OA). METHODS: MRI of the knee was performed at baseline, 15 months, and 30 months in 217 patients with primary knee OA (122 men, 95 women; mean +/- SD age 66.4 +/- 9.4 years). To assess mechanical alignment, long-limb films were obtained at 15 months. Subchondral bone marrow abnormalities, graded in the medial and lateral tibiofemoral joints, were defined as poorly marginated areas of increased signal intensity in the marrow on fat-suppressed, T2-weighted images. Cartilage morphologic features in the medial and lateral tibiofemoral joints were scored at all time points using a semiquantitative scale. For each of the medial and lateral compartments, generalized estimating equations were used to evaluate the longitudinal relationship of tibiofemoral BMLs to the tibiofemoral cartilage score, with adjustment for malalignment. RESULTS: Fifty-seven percent of knees had BMLs at baseline, of which 99% remained the same or increased in size at followup. Knee compartments with a higher baseline BML score had greater cartilage loss. An increase in BMLs was strongly associated with further worsening of the cartilage score. Enlarging or new BMLs occurred mostly in malaligned limbs, on the side of the malalignment (e.g., new medial BMLs in varus-aligned knees). The association of BML change with medial tibiofemoral cartilage loss was not significant after adjusting for alignment. CONCLUSION: Lesions of the bone marrow are unlikely to resolve and often get larger over time. Compared with BMLs that stay the same, enlarging BMLs are strongly associated with more cartilage loss. Furthermore, any change in BML is mediated by limb alignment.

Aged↗

PubMed2006

Connective tissue growth factor/CCN2 overexpression in mouse synovial lining results in transient fibrosis and cartilage damage.

OBJECTIVE: Characteristics of osteoarthritis (OA) include cartilage damage, fibrosis, and osteophyte formation. Connective tissue growth factor (CTGF; also known as CCN2), is found in high levels in OA chondrocytes and is frequently involved in fibrosis, bone formation, and cartilage repair. The present study was therefore undertaken to investigate the potential role of CTGF in OA pathophysiology. METHODS: We transfected the synovial lining of mouse knee joints with a recombinant adenovirus expressing human CTGF and measured synovial fibrosis and proteoglycan content in cartilage on days 1, 3, 7, 14, and 28. Messenger RNA (mRNA) expression in synovium and cartilage was measured on days 3, 7, and 21. RESULTS: CTGF induced synovial fibrosis, as indicated by accumulation of extracellular matrix and an increase in procollagen type I-positive cells. The fibrosis reached a maximum on day 7 and had reversed by day 28. Levels of mRNA for matrix metalloproteinase 3 (MMP-3), MMP-13, ADAMTS-4, ADAMTS-5, tissue inhibitor of metalloproteinases 1 (TIMP-1), and transforming growth factor beta were elevated in the fibrotic tissue. TIMP-1 expression was elevated on day 3, while expression of other genes did not increase until day 7 or later. CTGF induced proteoglycan depletion in cartilage as early as day 1. Maximal depletion was observed on days 3-7. Cartilage damage was reduced by day 28. A high level of MMP-3 mRNA expression was found in cartilage. CTGF overexpression did not induce osteophyte formation. CONCLUSION: CTGF induces transient fibrosis that is reversible within 28 days. Overexpression of CTGF in knee joints results in reversible cartilage damage, induced either by the high CTGF levels or via factors produced by the CTGF-induced fibrotic tissue.

Animals↗

PubMed2006

Lack of association between chondrocalcinosis and increased risk of cartilage loss in knees with osteoarthritis: results of two prospective longitudinal magnetic resonance imaging studies.

OBJECTIVE: To evaluate the relationship between chondrocalcinosis and the progression of knee osteoarthritis (OA) using longitudinal magnetic resonance imaging (MRI) assessments. METHODS: Longitudinal knee MRIs were obtained in the Boston OA Knee Study (BOKS) and in the Health, Aging and Body Composition (Health ABC) Study. Chondrocalcinosis was determined as present or absent on baseline knee radiographs. Cartilage morphology was graded on paired longitudinal MRIs using the Whole-Organ Magnetic Resonance Imaging Score in 5 cartilage subregions of each of the medial and lateral tibiofemoral joints. Cartilage loss in a subregion was defined as an increase in the cartilage score of > or = 1 (0-4 scale). The risk for change in the number of subregions with cartilage loss was assessed using Poisson regression, with generalized estimating equations to account for correlations. Analyses were adjusted for age, sex, body mass index, baseline cartilage score, and presence of damaged menisci. RESULTS: In BOKS, 23 of the 265 included knees (9%) had chondrocalcinosis. In Health ABC, 373 knees were included, of which 69 knees (18.5%) had chondrocalcinosis. In BOKS, knees with chondrocalcinosis had a lower risk of cartilage loss compared with knees without chondrocalcinosis (adjusted risk ratio [RR] 0.4, 95% confidence interval [95% CI] 0.2-0.7) (P = 0.002), and there was no difference in risk in Health ABC (adjusted RR 0.9, 95% CI 0.6-1.5) (P = 0.7). Stratification by intact versus damaged menisci produced similar results within each cohort. CONCLUSION: In knees with OA, the presence of chondrocalcinosis was not associated with increased cartilage loss. These findings do not support the hypothesis that chondrocalcinosis worsens OA progression.

Aged↗

PubMed1993

The effect of naproxen and interleukin-1 on proteoglycan catabolism and on neutral metalloproteinase activity in normal articular cartilage in vitro.

The events in inflammatory and degenerative joint diseases involve major changes in the metabolic events in the articular cartilage. The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on articular cartilage metabolism remain unclear, however. The objective of this catabolism of proteoglycans in articular cartilage explants maintained in culture. Release of proteoglycan from the cartilage was compared with release of neutral metalloproteinase activity. The effect of the drug also was determined on the IL-1-stimulated release of proteoglycan and neutral metalloproteinase activity from the explants. At concentrations that included those present in synovial fluids of patients treated with the drug, naproxen sodium was found to suppress the release of proteoglycan and neutral metalloproteinase activity from the articular cartilage extracts. This is in contrast to the well-documented effect of interleukin-1 (IL-1), which was shown to stimulate release of proteoglycan and neutral metalloproteinase activity from articular cartilage. The effect of naproxen sodium on the IL-1-stimulated release was to suppress, but not totally overcome, the increased release of proteoglycan and neutral metalloproteinase activity. In summary, these in vitro studies of cartilage metabolism indicate that naproxen sodium has the potential to suppress catabolic activities in articular cartilage, including those that are motivated by IL-1.

Animals↗

PubMed1988

1,25-Dihydroxyvitamin D3 stimulates avian and mammalian cartilage growth in vitro.

We addressed the question of whether 1,25-dihydroxyvitamin D3 (1,25-(OH)2D) could directly stimulate cartilage growth in vitro. Pelvic leaflets from chick embryos and scapular growth plates from fetal pigs were organ cultured in serum-free medium in the presence and absence of 1,25-(OH)2D. After 3 days of incubation, 1,25-(OH)2D had increased the pelvic cartilage wet weight 42% and the dry weight 32% above the weight of cartilages incubated in medium alone. 1,25-(OH)2D (10(-9) M-10(-12) M) caused a dose-dependent increase in weight, with maximal increases at 10(-9) M. Furthermore, two deuterized derivatives of 1,25-(OH)2D, 26,27-D6-1,25-(OH)2D3 and 24,26,27-D8-1,25-(OH)2D3, stimulated pelvic cartilage growth in vitro. 26,27-D6-1,25-(OH)2D stimulated increases in growth plate weight above growth plates incubated in medium alone. 26,27-D6-1,25-(OH)2D3 appeared to be potent at lower concentrations than 1,25-(OH)2D on growth plate cartilage. Thus, 1,25-(OH)2D stimulated in vitro growth in two growing cartilage models, the avian pelvic cartilage and the mammalian scapular growth plate cartilage.

Animals↗

PubMed1990

Long-term organ culture of embryonic chick femora: a system for investigating bone and cartilage formation at an intermediate level of organization.

Bone organ culture is an experimental system in which skeletal cells remain within their extracellular matrix but are removed from systemic influences. Femurs from 14-day-old chick embryos, which contain bone and cartilage matrix in approximately equal proportions, were cultured for up to 9 days in a serum-free medium. Cell proliferation, differentiation into chondrocytes and osteoblasts, formation of bone and cartilage matrix, and in vitro mineralization as well as bone and cartilage resorption were assessed using histologic and analytic methods. Particular attention was paid to the differences between cartilage and bone growth and to interpreting analytic data in the light of histologic observations. The first 2 days of culture represented an "adaptation" period, characterized by the release of intracellular enzymes into the culture medium, probably as a consequence of cell breakdown. Days 3-9 in culture represented a period of "steady growth" during which skeletal cells continued to multiply in the absence of fetal serum and to secrete large amounts of bone and cartilage matrix. De novo mineralization could be induced by Ca-beta-glycerophosphate, but calcium deposits in tissues other than bone and cartilage were also induced. Resorption of bone or cartilage matrix was virtually absent. Bone organ culture facilitates the study of bone and cartilage formation at an intermediate level of organization and thereby provides the necessary link between in vivo studies and investigations at the cellular level.

Acid Phosphatase↗

PubMed2002

Tissue inhibitor of metalloproteinases-4 (TIMP-4) gene expression is increased in human osteoarthritic femoral head cartilage.

Tissue inhibitor of metalloproteinases-4 (TIMP-4), the newest member of the TIMP family, blocks the activities of several matrix metalloproteinases (MMPs) implicated in the arthritic cartilage erosion. By utilizing semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry, we investigated whether the TIMP-4 gene is expressed in human non-arthritic and osteoarthritic (OA) cartilage. Directly analyzed femoral head cartilage showed TIMP-4 RNA expression in 2 of 9 non-arthritic and 12 of 14 OA patients. Femoral head cartilage from 6 of 9 OA patients had elevated TIMP-4 protein compared to the low-level expression in 3 of 8 non-arthritic controls. In most patients, there was correlation between TIMP-4 RNA and protein expression. TIMP-4 protein was also detected immunohistochemically in the upper zone of OA cartilage. The widespread TIMP-4 RNA and protein expression and augmentation in femoral OA cartilage suggests its important role in joint tissue remodeling and pathogenesis of OA. Increased TIMP levels in arthritic cartilage may not be a sufficiently effective defense against cartilage resorption by excessive multiple MMPs and aggrecanases.

Aged↗

PubMed1993

Cultivation of cell-polymer cartilage implants in bioreactors.

Cartilage implants for potential use in reconstructive or orthopedic surgery can be created by growing isolated cartilage cells (chondrocytes) in vitro on synthetic, biodegradable polymer scaffolds. The scaffolds provide specific three-dimensional structures which support cell proliferation and biodegrade in a controlled fashion in parallel to cellular regeneration of cartilaginous tissue. Cartilage implants based on chondrocytes and fibrous polyglycolic acid scaffolds were recently shown to closely resemble normal cartilage histologically as well as with respect to cell density and matrix composition (collagen, glycosaminoglycan) [Freed et al., J Biomed Mater Res 27:11-23, 1993a]. These findings form the basis for developing straightforward procedures to obtain implants for clinical use from small, autologous cartilage specimens without any limitations in terms of availability of donor tissue or implant dimensions. Chondrocyte growth and cartilage matrix regeneration on polymer scaffolds are interdependent and also depend on in vitro tissue culture conditions. Under static culture conditions, cell growth rates are diffusionally limited due to increasing cell mass and decreasing effective implant porosity resulting from cartilage matrix regeneration. Optimization of the in vitro culture environment is thus essential for the cultivation of large, clinically useful cartilage implants. Preliminary studies indicate that major improvements can be achieved using bioreactors that provide efficient mass transfer and controlled shear rates at the cell and implant surfaces.

Biotechnology↗