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PubMed2006

Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage.

Cartilage destruction in osteoarthritis (OA) is thought to be mediated by two main enzyme families; the matrix metalloproteinases (MMPs) are responsible for cartilage collagen breakdown, whereas enzymes from the 'a disintegrin and metalloproteinase domain with thrombospondin motifs' (ADAMTS) family mediate cartilage aggrecan loss. Tissue inhibitors of metalloproteinases (TIMPs) regulate the activity of these enzymes. Although cartilage destruction in OA might be driven by the chondrocyte, low-grade synovitis is reported in patients with all grades of this disease. Our earlier work profiling these gene families in cartilage identified a number of genes that are regulated in OA, which are hence implicated in the disease process. Because the synovium might contribute to cartilage-matrix destruction in OA, we have extended the screening in the current study. We have profiled MMP, ADAMTS and TIMP genes in both cartilage and synovium from patients with either OA of the hip or a fracture to the neck of femur (NOF), giving a more complete picture of proteolysis in this disease. The four most significantly upregulated genes (P < 0.0001) in OA synovium compared to the fractured NOF are MMP28, ADAMTS16, ADAMTS17 and TIMP2. For MMP9, MMP10, MMP12, MMP17, MMP23, MMP28, ADAMTS4, and ADAMTS9, there is a significant correlation between expression levels in the synovium and cartilage, suggesting similar mechanisms of regulation. Additionally, we have shown that in cartilage the median level of steady-state mRNA for MMP13 is approximately 20-fold higher than MMP28 and approximately 1,500-fold higher than ADAMTS16, with expression of this latter gene approximately 150-fold higher in synovium than cartilage. This study is the most comprehensive analysis of the metzincin family of proteinases in the joint to date and has identified several proteinase genes not previously reported to be expressed or regulated in synovium.

ADAM Proteins↗
PubMed1989

Effects of dexamethasone and vitamin D3 on cartilage differentiation in a clonal chondrogenic cell population.

We have investigated the regulation of chondroblast/chondrocyte differentiation using a unique clonal cell population, designated RCJ 3.1C5 (C5), which differentiates into discrete three-dimensional cartilage nodules when grown in the presence of 15% fetal calf serum. Histologically, the nodules resembled hyaline cartilage; they contained large rounded chondrocytes surrounded by a refractile matrix which stained intensely with Alcian blue, exhibited metachromasia after Toluidine blue staining, and stained with an antibody against type II collagen. The cartilage nodules that formed did not mineralize, despite the presence of organic phosphate in the culture medium. The synthetic glucocorticoid dexamethasone (DEX) increased the number of cartilage nodules formed in a dose-dependent manner (ED50, approximately 10(-9) M), with a maximal stimulatory dose of 10(-8) M. DEX had no effect on the population doubling time and saturation density. The effects of DEX on the number of cartilage nodules were similar whether it was added from the beginning of the culture period (starting during exponential growth) or at confluence. In contrast, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibited cartilage nodule formation in a dose-dependent manner (IC50, approximately 5 x 10(-10) M), with maximum inhibition at 10(-7) M. In addition, 1,25-(OH)2D3 decreased cell proliferation and saturation density. Equimolar doses of the vitamin D3 metabolites 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 had no effect. C5 cells treated with 1,25-(OH)2D3 in the absence of DEX during the exponential growth phase exhibited a reduced capacity to form cartilage nodules upon subsequent exposure to DEX. At confluence, before cartilage nodules had formed, C5 cells responded to PTH and prostaglandin-E2 with increases in intracellular cAMP of about 10- and 95-fold respectively. After cartilage nodules were present, prostaglandin-E2 responsiveness decreased to about 25-fold, whereas there was no significant change in PTH responsiveness. DEX decreased the population alkaline phosphatase levels at all times measured, whereas 1,25-(OH)2D3 had a biphasic effect: an increase at 5 days in culture, followed by a decrease at later times in culture. These data indicate that the clonal cell line RCJ 3.1C5 is a useful model system in which to investigate cartilage differentiation.

Adenylyl Cyclases↗
PubMed1996

The influence of loading time and lubricant on the friction of articular cartilage.

Friction of cartilage on metal, metal on cartilage and cartilage on cartilage contact configurations, within a mixed lubrication regime, was measured using synovial fluid, Ringer's solution or with no lubricant present. The main test variable was the period of stationary loading which ranged from 5 s to 45 min, prior to sliding and consequently measuring friction. The coefficient of friction rose gradually with increasing stationary loading time, up to a value of approximately 0.3 at 45 min for all the contact configurations. Following the re-application of load, after short periods of load removal, friction was also found to drop sharply. The flow of liquid in the biphasic cartilage and load carriage by the fluid phase was highlighted as being an important factor in reducing friction within the mixed or boundary lubrication regime. Movement of the contact zone over the cartilage counterface ensured very low friction as the slider moved over fully hydrated cartilage. For the cartilage--cartilage contacts synovial fluid significantly reduced friction compared to Ringer's solution. This was attributed to an effective boundary lubrication action, which was not as effective for the cartilage--metal contacts.

Animals↗
PubMed2006

Effect of Betula platyphylla var. japonica on proteoglycan release, type II collagen degradation, and matrix metalloproteinase expression in rabbit articular cartilage explants.

Articular cartilage is a potential target for drugs designed to inhibit the activity of matrix metalloproteinases (MMPs) to stop or slow the destruction of proteoglycan and collagen in the cartilage extracellular matrix. The purpose of this study was to investigate the effects of Betula platyphylla var. japonica on inhibiting the release of glycosaminoglycan (GAG), the degradation of collagen, and MMP expression and activity in rabbit articular cartilage explants. Interleukin-1alpha (IL-1alpha) rapidly induced GAG, but collagen was much less readily released from cartilage explants. Betula platyphylla var. japonica significantly inhibited GAG and collagen release in a concentration-dependent manner. Betula platyphylla var. japonica dose-dependently inhibited MMP-3 and MMP-13 expression and activities from IL-1alpha-treated cartilage explant culture when tested at concentrations ranging from 0.02 to 0.2 mg/ml. Betula platyphylla var. japonica had no harmful effect on chondrocyte viability or cartilage morphology in cartilage explants. Histological analysis indicated that Betula platyphylla var. japonica reduced the degradation of the cartilage matrix compared with that of IL-1alpha-treated cartilage explants. These results indicate that Betula platyphylla var. japonica inhibits the degradation of proteoglycan and collagen through the down regulation of MMP-3 and MMP-13 expression and activities without affecting the viability or morphology of IL-1alpha-stimulated rabbit articular cartilage explants.

Animals↗
PubMed2003

Purification of matrix Gla protein from a marine teleost fish, Argyrosomus regius: calcified cartilage and not bone as the primary site of MGP accumulation in fish.

Matrix Gla protein (MGP) belongs to the family of vitamin K-dependent, Gla-containing proteins, and in mammals, birds, and Xenopus, its mRNA was previously detected in extracts of bone, cartilage, and soft tissues (mainly heart and kidney), whereas the protein was found to accumulate mainly in bone. However, at that time, it was not evaluated if this accumulation originated from protein synthesized in cartilage or in bone cells because both coexist in skeletal structures of higher vertebrates and Xenopus. Later reports showed that MGP also accumulated in costal calcified cartilage as well as at sites of heart valves and arterial calcification. Interestingly, MGP was also found to accumulate in vertebra of shark, a cartilaginous fish. However, to date, no information is available on sites of MGP expression or accumulation in teleost fishes, the ancestors of terrestrial vertebrates, who have in their skeleton mineralized structures with both bone and calcified cartilage. To analyze MGP structure and function in bony fish, MGP was acid-extracted from the mineralized matrix of either bone tissue (vertebra) or calcified cartilage (branchial arches) from the bony fish, Argyrosomus regius, separated from the mineral phase by dialysis, and purified by Sephacryl S-100 chromatography. No MGP was recovered from bone tissue, whereas a protein peak corresponding to the MGP position in this type of gel filtration was obtained from an extract of branchial arches, rich in calcified cartilage. MGP was identified by N-terminal amino acid sequence analysis, and the resulting protein sequence was used to design specific oligonucleotides suitable to amplify the corresponding DNA by a mixture of reverse transcription-polymerase chain reaction (RT-PCR) and 5'rapid amplification of cDNA (RACE)-PCR. In parallel, ArBGP (bone Gla protein, osteocalcin) was also identified in the same fish, and its complementary DNA cloned by an identical procedure. Tissue distribution/accumulation was analyzed by Northern blot, in situ hybridization, and immunohistochemistry. In mineralized tissues, the MGP gene was predominantly expressed in cartilage from branchial arches, with no expression detected in the different types of bone analyzed, whereas BGP mRNA was located in bone tissue as expected. Accordingly, the MGP protein was found to accumulate, by immunohistochemical analysis, mainly in the extracellular matrix of calcified cartilage. In soft tissues, MGP mRNA was mainly expressed in heart but in situ hybridization, indicated that cells expressing the MGP gene were located in the bulbus arteriosus and aortic wall, rich in smooth muscle and endothelial cells, whereas no expression was detected in the striated muscle myocardial fibers of the ventricle. These results show that in marine teleost fish, as in mammals, the MGP gene is expressed in cartilage, heart, and kidney tissues, but in contrast with results obtained in Xenopus and higher vertebrates, the protein does not accumulate in vertebra of non-osteocytic teleost fish, but only in calcified cartilage. In addition, our results also indicate that the presence of MGP mRNA in heart tissue is due, at least in fish, to the expression of the MGP gene in only two specific cell types, smooth muscle and endothelial cells, whereas no expression was found in the striated muscle fibers of the ventricle. In light of these results and recent information on expression of MGP gene in these same cell types in mammalian aorta, it is likely that the levels of MGP mRNA previously detected in Xenopus, birds, and mammalian heart tissue may be restricted to regions rich in smooth muscle and endothelial cells. Our results also emphasize the need to re-evaluate which cell types are involved in MGP gene expression in other soft tissues and bring further evidence that fish are a valuable model system to study MGP gene expression and regulation.

Amino Acid Motifs↗
PubMed1981

Cartilage response to plasma and plasma somatomedin activity in rats related to growth before and after birth.

Cartilage response to plasma, plasma somatomedin activity, body weight and length were measured in rats from 15 days of fetal age to 37 days postnatally. The metabolic activity of costal cartilage was assessed by the incorporation of [35S]sulphate in basal medium and after stimulation by plasma. It was found that (a) A significant stimulation of isotope uptake above basal levels occurred in the presence of 15% standard adult rat plasma at every age studied. (b) The degree of stimulation, a measure of cartilage sensitivity to plasma growth factors, increased through the latter part of fetal life but fell after birth. A high degree of cartilage stimulation was seen on day 6 of postnatal life. (c) The changes in cartilage sensitivity and in the stimulated isotope uptake, resembled the changes observed in growth rate for body weight, nose-rump length and tail length. (d) Plasma somatomedin activity measured by the pig costal cartilage assay was low in the fetus and neonate but rose to adult values 9 days after birth. However, plasma from fetal or neonatal rats tested on cartilage from rats of the same age was equipotent to adult rat plasma. (e) Plasma from hypophysectomized adult rats had a low potency in stimulating isotope uptake by neonatal rat cartilage but was equipotent to normal adult rat plasma in its action on fetal cartilage. (f) The action of plasma from hypophysectomized rats on fetal cartilage was unaffected by dialysis but was destroyed by incubation with trypsin.

Animals↗
PubMed2002

Production of cartilage link protein by human granulosa-lutein cells.

Link protein (LP), an extracellular matrix protein in cartilage, stabilizes aggregates of hyaluronic acid (HA) and proteoglycans, including aggrecan and inter-alpha-trypsin inhibitor (ITI). We have shown previously that cartilage LP is present in the maturing rat and mouse ovary. In the present study, we have employed immunohistochemistry to examine the anatomical distribution of cartilage LP in the human ovary. The expression of cartilage LP was selectively detected in the cells within the granulosa compartment of the preovulatory dominant follicle. The HA-positive granulosa-lutein cells were found to be a cartilage LP-positive subpopulation. We subsequently studied the in vitro expression of cartilage LP in cultured human granulosa-lutein cells obtained at oocyte retrieval for in vitro fertilization. Analysis of cultured cells by enzyme-linked immunoaffinity assay, Western blotting and immunofluorescence microscopy revealed that gonadotropin stimulates cartilage LP production. Time-course studies indicated that the cartilage LP production was induced as early as with gonadotropin stimulation for 2 h, and the effect was sustained up to 8 h. Western blot analysis further revealed the presence of the macroaggregates composed of HA, ITI and cartilage LP in the gonadotropin-stimulated granulosa-lutein cell extracts. Collectively, the present results raise the possibility that cartilage LP forms extracellular structures that may have a regulatory function in the developing follicle in the human ovary.

Adult↗
PubMed1994

Fat-suppressed spoiled GRASS imaging of knee hyaline cartilage: technique optimization and comparison with conventional MR imaging.

OBJECTIVE: We studied healthy volunteers with fat-suppressed three-dimensional (3D) spoiled gradient-recalled acquisition in the steady state (SPGR) to determine parameters that maximize positive contrast between knee articular cartilage and fluid, marrow fat, and muscle; and we compared the technique with conventional MR imaging sequences. The purpose was to determine if fat-suppressed 3D SPGR imaging is useful for detecting abnormalities of the articular cartilages. SUBJECTS AND METHODS: The knees of 10 healthy volunteers were imaged in the axial plane. Fat-suppressed 3D SPGR imaging was performed with a TR of 60 msec, a TE ranging from 5 to 15 msec, and a flip angle ranging from 20 degrees to 80 degrees. This was followed by a similar set of fat-suppressed two-dimensional (2D) SPGR images, and conventional T1- and T2-weighted spin-echo and multiplanar gradient studies. Contrast-to-noise (C/N) ratios were determined for cartilage versus a saline fluid phantom, marrow fat, and muscle. Optimal parameters were determined both quantitatively and by a blinded subjective analysis. RESULTS: A TE of 5 msec and a flip angle of 40 degrees demonstrated the greatest C/N ratio between the signals for cartilage and for fluid, marrow, and muscle. C/N ratios in the 3D sequences were higher than in the 2D, spin-echo, and gradient series, although the absolute C/N ratio values for the T2-weighted spin-echo sequence were higher than those for the 3D fat-suppressed SPGR sequence. Subjective analysis showed articular cartilage to have a consistent trilaminar appearance, and independent interpreters favored a 3D fat-suppressed SPGR sequence with a TE of 5 msec and a flip angle of 40 degrees. Three subjects with incidental joint fluid had C/N ratios within a 95% confidence range for cartilage versus the fluid phantom. CONCLUSION: When a fat-suppressed 3D SPGR sequence of 60/5/40 degrees (TR/TE/flip angle) is used, MR images can show high positive contrast between articular hyaline cartilage and adjacent structures. This convenient technique is different from standard MR imaging sequences because it demonstrates greater signal intensity in cartilage than in fluid, marrow fat, and muscle, and because it consistently shows an organized internal architecture of hyaline cartilage. Fat-suppressed 3D SPGR imaging therefore has promise for detecting abnormalities of the articular cartilage.

Adult↗
PubMedDate not supplied

Compressive biomechanical properties of human nasal septal cartilage.

BACKGROUND: Nasal septal cartilage is frequently used in nasal reconstruction and is a common source of chondrocytes for cartilage tissue engineering. The biomechanical properties of septal cartilage have yet to be fully defined and this limits the ability to compare it to the various alternative tissue-implant materials or tissue-engineered neocartilage. Given the unique structure and orientation of the septum within the nose, we sought to investigate anisotropic behaviors of septal cartilage in compression and correlate this to the concentration of glycosaminoglycans (GAG) and collagen within the cartilage. METHODS: Human nasal septal cartilage specimens were tested in confined compression, with each sample analyzed in a medial orientation and also either a vertical or caudal-cephalic orientation, with the order of tests randomized. The equilibrium confined compression (aggregate) modulus, HAO, and the permeability, kp, at different offset compression levels were obtained for each compression test. After testing, the cartilage samples were solubilized, and the concentrations of GAG and collagen were obtained. RESULTS: Forty-nine compression tests (24 medial, 12 vertical, 13 caudal-cephalic) were run on cartilage specimens obtained from 21 patients. There was a significant effect of orientation on compression modulus, HAO, with the vertical (0.7 +/- 0.12 MPa) and caudal-cephalic (0.66 +/- 0.01 MPa) orientations being significantly stiffer (p = 0.05) than the medial orientation (0.44 +/- 0.04 MPa). There was a trend of an orientation effect on kp at 15% offset compression (p = 0.12) and a borderline significant effect of orientation on kp at 30% offset compression (p = 0.05), demonstrating the M orientation to be more permeable than both the vertical and caudal-cephalic orientations. Both univariate and multivariate analysis did not demonstrate a significant effect of order of compression, age, gender, thickness, dry/wet weight, GAG, or collagen on either HAO, or kp values (p > 0.05). CONCLUSION: This study provides new information on the compressive properties of septal cartilage along different axes of compression. The results demonstrate that human septal cartilage is anisotropic; the compressive stiffness is higher in the vertical and caudal-cephalic orientations than in the medial orientation. Additionally, the medial orientation tends to have the greatest permeability. The data obtained in this study provide a reference to which various craniofacial reconstruction materials and tissue-engineered neocartilage can be compared.

Adolescent↗
PubMed1999

Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments.

There are few candidates for biochemical pathways that either initiate or amplify catabolic processes involved in osteoarthritis (OA). Perhaps, one of the most likely sources for such pathways may be within the extracellular matrix itself. This review focuses on an example of how specific degradation products of the extracellular matrix of cartilage, produced during proteolytic damage, have the potential to enhance OA-like processes. In this example, these products can induce or activate other factors, such as catabolic cytokines, that amplify the damage. The damage, in turn, enhances levels of the degradation products themselves, as in a positive feedback loop. Since these products are derived from the cartilage matrix, they could be considered barometers of the health of the cartilage that signal to the chondrocyte, through outside to inside signaling, the health or status of the surrounding matrix. The best example and most characterized system is that of fragments of the matrix protein, fibronectin (Fn), although as discussed later, other recently discovered fragment systems may also have the potential to regulate cartilage metabolism. In the case of Fn fragments (Fn-fs), the Fn-fs enhance levels of catabolic cytokines as in OA and, thus, are potentially earlier damage mediators than catabolic cytokines. The Fn-fs up-regulate matrix metalloproteinase (MMP) expression, significantly enhance degradation and loss of proteoglycan (PG) from cartilage and temporarily suppress PG synthesis, all events observed in OA. However, this Fn-f system may be involved in normal cartilage homeostasis as well. For example, low concentrations of Fn-fs enhance anabolic activities and could play a role in normal homeostasis. This system may also be involved in not only amplifying damage but also coupling damage to repair. For example, high concentrations of Fn-fs that might arise in OA temporarily offset the anabolic response of lower Fn-f concentrations and cause short-term enhanced catabolic events that are followed by slowly increasing anabolic responses. Such effects would be expected for mediators with roles in regulation of metabolism in both normal or diseased cartilage. Other products of matrix degradation have also been shown to regulate cartilage metabolism. A common mechanistic theme to these systems may be that they perturb the cartilage matrix and directly or indirectly alter function of specific receptors involved in metabolism. These concepts illustrate the potential of the cartilage matrix to regulate its composition in both health and disease.

Animals↗
PubMed2000

Functional adaptation of equine articular cartilage: the formation of regional biochemical characteristics up to age one year.

Biochemical heterogeneity of cartilage within a joint is well known in mature individuals. It has recently been reported that heterogeneity for proteoglycan content and chondrocyte metabolism in sheep develops postnatally under the influence of loading. No data exist on the collagen network in general or on the specific situation in the horse. The objective of this study was to investigate the alterations in equine articular cartilage biochemistry that occur from birth up to age one year, testing the hypothesis that the molecular composition of equine cartilage matrix is uniform at birth and biochemical heterogeneity is formed postnatally. Water content, DNA content, glycosaminoglycan content (GAG) and biochemical characteristics of the collagen network (collagen content, hydroxylysine content and hydroxylysylpyridinoline [HP] crosslinks) were measured in immature articular cartilage of neonatal (n = 16), 5-month-old foals (n = 16) and yearlings (n = 16) at 2 predefined differently loaded sites within the metacarpophalangeal joint. Statistical differences between sites were analysed by ANOVA (P<0.01), and age correlation was tested by Pearson's product moment correlation analysis (P<0.01). In neonatal cartilage no significant site differences were found for any of the measured biochemical parameters. This revealed that the horse has a biochemically uniform joint (i.e. the cartilage) at birth. In the 5-month-old foals and yearlings, significant site differences, comparable to those in the mature horse, were found for DNA, GAG, collagen content and hydroxylysine content. This indicates that functional adaptation of articular cartilage to weight bearing for these biochemical parameters takes place during the first months postpartum. Water content and HP crosslinks showed no difference between the 2 sites from neonatal horses, 5-month-old animals and yearlings. At both sites water, DNA and GAG decreased during maturation while collagen content, hydroxylysine content and HP crosslinks increased. We propose that a foal is born with a uniform biochemical composition of cartilage in which the functional adaptation to weight bearing takes place early in life. This adaptation results in biochemical and therefore biomechanical heterogeneity and is thought to be essential to resist the different loading conditions to which articular cartilage is subjected during later life. As collagen turnover is extremely low at mature age, an undisturbed functional adaptation of the collagen network of articular cartilage at a young age may be of significant importance for future strength and resistance to injury.

Age Factors↗
PubMed2003

Estimates of heritability for ossification of the cartilages of the front feet in the Finnhorse.

REASONS FOR PERFORMING STUDY: Ossification of the cartilages in the foot is common in coldblooded horses, but prevalence as well as ossification pattern varies between breeds; research on estimation of heritability for the condition has been limited. OBJECTIVES: Our purpose was to calculate estimates of 1) heritability for ossification parameters of the cartilages in the front feet of the Finnhorse and 2) genetic correlations between the different ossification parameters. METHODS: Estimates of heritability for different ossification parameters of the cartilages in the front feet and of genetic correlations between different parameters were evaluated in data consisting of dorsopalmar radiographs of the front feet and pedigree up to the fourth generation of 964 Finnhorses (age > or = 2 years; 345 females and 619 males). Ossification at the base of the cartilages and total ossification, including separate centres of ossification, were graded 0-5 according to the most proximal point of ossification and the presence of separate centres of ossification was recorded separately. The data were analysed using a model including a fixed sex-age subclass effect and a random animal effect. Variance and covariance components were estimated with the restricted maximum likelihood (REML) method assuming an animal model. RESULTS: Females had more ossification than males and this difference increased with age. The ossification in the medial cartilages progressed significantly with age in females but not in males. In the lateral cartilages, the increase in ossification with age was evident in both sexes. Separate centres of ossification were an incidental finding. Estimates of heritability for the ossification parameters varied slightly between the cartilages as well as between the front feet. For total ossification, the estimates of heritability varied between 0.31 (right lateral) and 0.50 (left medial) and were slightly higher for ossification at the base of the cartilages. High genetic correlations were found for total ossification between the medial and lateral cartilages in the foot and for parallel ossification parameters between the right and left foot. CONCLUSIONS: The estimates of heritability were relatively high, and both cartilages and front feet have a similar genetic tendency to ossify. POTENTIAL RELEVANCE: This information is useful in further studies assessing other factors contributing to the ossification process and also in the planning and modifying breeding programmes.

Aging↗
PubMed1999

Articular cartilage compressive stiffness following oophorectomy or treatment with 17beta-estradiol in young postpubertal rabbits.

BACKGROUND: Changes in estrogen concentrations during adolescence (contraceptives, secondary amenorrhea) may influence cartilage mechanics and therefore its capacity to respond adequately to physical demands. The purpose of this study was to investigate the influence of oophorectomy or continuous administration of estradiol on cartilage compressive properties in an immature animal model. METHODS: Young postpubertal female New Zealand white rabbits were either oophorectomized (n=9) or underwent a sham-operation (n=8). The sham-operated animals received in addition a daily dosage of 4 mg 17beta-estradiol orally starting 3 weeks after surgery until death. After 5 months the animals were killed, and cartilage compressive properties (ramp and creep moduli) were determined at 4 defined knee joint regions by in situ indentation tests. Five age-matched rabbits were used as controls. RESULTS: Femoral cartilage stiffness (ramp and 15-s creep moduli) and thickness in oophorectomized animals were significantly higher than those in controls or estradiol-treated animals (p<0.05 and less), but there was no difference between the latter groups. Tibial cartilage showed less obvious treatment-dependent differences. The cartilage in the medial compartment was thicker than in the lateral one, and femoral cartilage was thinner than tibial cartilage (p<0.00005), irrespective of the treatment. CONCLUSIONS: Oophorectomy during adolescence led to increased femoral cartilage thickness and stiffness. The relevance of these findings for the development of cartilage disease has to be elucidated in the future.

Age Factors↗
PubMed2000

Damage control mechanisms in articular cartilage: the role of the insulin-like growth factor I axis.

Articular chondrocytes maintain cartilage throughout life by replacing lost or damaged matrix with freshly synthesized material. Synthesis activity is regulated, rapidly increasing to well above basal levels in response to cartilage injury. Such responses suggest that synthesis activity is linked to the rate of matrix loss by endogenous "damage control" mechanisms. As a major stimulator of matrix synthesis in cartilage, insulin-like growth factor I (IGF-I) is likely to play a role in such mechanisms. Although IGF-I is nearly ubiquitous, its bioavailability in cartilage is controlled by IGF-I binding proteins (IGFBPs) secreted by chondrocytes. IGFBPs are part of a complex system, termed the IGF-I axis, that tightly regulates IGF-I activities. For the most part, IGFBPs block IGF-I activity by sequestering IGF-I from its cell surface receptor. We recently found that the expression of one binding protein, IGFBP-3, increases with chondrocyte age, paralleling an age-related decline in synthesis activity. In addition, IGFBP-3 is overexpressed in osteoarthritic cartilage, leading to metabolic disturbances that contribute to cartilage degeneration. These observations indicate that IGFBP-3 plays a crucial role in regulating matrix synthesis in cartilage, and suggest that cartilage damage control mechanisms may fail due to age-related changes in IGFBP-3 expression or distribution. Our investigation of this hypothesis began with immunolocalization studies to determine the tissue distribution of IGFBP-3 in human cartilage. We found that IGFBP-3 accumulated around chondrocytes in the pericellular/territorial matrix, where it co-localized with fibronectin, but not with the other matrix proteins tenascin-C and type VI collagen. This result suggested that the IGFBP-3 distribution is determined by binding to fibronectin. Binding studies using purified proteins demonstrated that IGFBP-3 does in fact bind to fibronectin, but not to tenascin-C or type VI collagen. Finally, we investigated the metabolic effects of fibronectin and IGFBP-3 in a chondrocyte culture system. These experiments showed that fibronectin enhanced the inhibitory effect that low concentrations of IGFBP-3 had on matrix synthesis. Taken together, these observations confirm that IGFBP-3-fibronectin interactions affect the IGF-I axis, and they indicate that IGF-I is stored in the chondrocyte territorial matrix through binding to a complex of IGFBP-3 and intact fibronectin. This arrangement may play an important role in cartilage damage control mechanisms. The local increase in matrix synthesis following injury could result from damage-induced IGF-I release from such pools. An age-related failure to organize this system may contribute to degenerative disease.

Adult↗
PubMed1994

Synthesis of a phenotypically abnormal type XI: type II collagen ratio by chondrocytes from canine osteoarthritic cartilage.

Collagen synthesis by osteoarthritic cartilage from dogs that had undergone anterior cruciate ligament transection was measured in short-term organ cultures and chondrocyte suspension cultures. Slices of osteoarthritic cartilage from unstable knees 2, 6 or 12 weeks after anterior cruciate ligament transection converted approximately 10% of the total incorporated 14C-proline to 14C-hydroxyproline, while the value for cartilage from the contralateral knee or from knees of normal control dogs was generally less than 1%. The increase in collagen synthesis in the osteoarthritic cartilage was not related to the duration of knee instability, but was greater in grossly fibrillated cartilage than in the total pooled cartilage from the osteoarthritic joint. The collagen that was synthesized was predominantly type II, although some type XI and/or type V collagen was also synthesized. Chondrocytes isolated from osteoarthritic knee cartilage of dogs 12 weeks after anterior cruciate ligament transection showed changes in collagen synthesis similar to those seen in the cartilage organ cultures. As in the organ culture studies, type II collagen was the predominant species synthesized. When cell-associated collagen was considered, type II collagen accounted for 87+/-7% of the total collagen synthesized and retained by the osteoarthritic chondrocytes. The corresponding value for cells from the contralateral knee was 63+/-10%. Since the collagen fiber in articular cartilage is a heteropolymer of type II, type XI and type IX collagen, it is likely that the newly synthesized collagens in this model of osteoarthritis form fibers that are phenotypically different from those in normal articular cartilage.

Animals↗
PubMed2002

Novel fluorescent compound (DDP) in calf, rabbit, and human articular cartilage and synovial fluid.

OBJECTIVE: To investigate the presence of and quantify 2,6-dimethyldifuro-8-pyrone (DDP), a novel fluorescent compound identified as in various calf, rabbit, and human tissue/fluid samples, to determine the DDP level in articular cartilage (AC) laminae, and to investigate the changes in cartilage DDP content with cartilage maturation. METHODS: Samples were obtained from calf (< 2 years), rabbit (< 2 weeks to 2 years) or human AC and synovial fluid (SF) as well as other non-cartilaginous tissues. SF and tissue samples were hydrolyzed with 6 M HCl (24 hours at 110 degrees C), lyophilized, and dissolved in HPLC mobile phase. DDP and collagen crosslink peaks were measured using a fluorescence detector at excitation and emission wavelengths of 295 and 395 nm, respectively. RESULTS: DDP was detected from calf metacarpophalangeal joint AC (362 +/- 48 pmol/mg dry weight), SF (4.5 +/- 0.3 pmol/microl SF), and intervertebral disc (24 +/- 4 pmol/mg). DDP was not detected in calf ligament, tendon, bone, ocular lens, cornea, or elastic cartilage. The DDP amount was greater in mid-deep cartilage lamina (448 +/- 63 pmol/mg) than superficial-mid lamina (129 +/- 52 pmol/mg) (p = 0.008). DDP level decreased with maturation in rabbit knee joint AC from 185 +/- 40 (< 2 weeks) to 27 +/- 3 (2 years) pmol/mg dry weight. DDP was not detected in adult rabbit ligament, tendon, meniscus, or bone. DDP was detected in human knee joint AC and SF. The DDP level in osteoarthritic lesions was present in lower concentrations (range: 0 to 96 pmol/mg dried AC) compared to intact AC (range: 63 to 236 pmol/mg) of the same knee. CONCLUSION: DDP is a hyaline cartilage specific compound present in all articular cartilage samples from various articulating joints/animal species. DDP level increases with AC depth and decreases with cartilage maturation. DDP is a potential indicator of cartilage metabolism during normal growth, ageing, and cartilage disease.

Aged↗
PubMed2002

Compartment differences in knee cartilage volume in healthy adults.

OBJECTIVE: It is unclear why there are compartmental differences in the risk of knee osteoarthritis (OA). We investigated whether there are compartment differences in the volume of knee cartilage in healthy persons and identified determinants of medial and lateral tibial cartilage volume. METHODS: A total of 166 healthy persons (age range 21-79 yrs, 58% female) with clinically and structurally normal knees were examined. Thickness and volume were determined for the medial and lateral tibial articular cartilages by processing images acquired in the sagittal plane using T1 weighted fat saturated magnetic resonance imaging on an independent work station. RESULTS: In every subject, the lateral tibial cartilage was thicker than medial cartilage (mean 6.43 +/- SD 1.25 mm vs 4.49 +/- 0.81 mm; p < 0.001), and the volume of cartilage was greater (2.34 +/- 0.70 ml vs 1.82 +/- 0.56 ml; p < 0.001). This effect persisted when values for men and women were analyzed separately. Both medial and lateral tibial cartilage volume and thickness were greater in men compared to women, independent of body mass index and bone size. The reduction in medial and lateral tibial cartilage volume and thickness was inversely related to the current level of physical activity. CONCLUSION: This study supports the knee compartment differences in cartilage volume recently reported in children. It is likely these differences are maintained throughout life. The possibility that the amount of knee cartilage in an individual is a risk factor for OA now needs to be tested in longitudinal studies.

Adult↗
PubMed2002

Ultrasonic characterization of articular cartilage.

Osteoarthrosis is the most important joint disease that threatens health of the musculoskeletal system of elderly people. Today, there is a need for sensitive, quantitative diagnostic methods for successful and early diagnosis of the disorder. In the present study, we aimed at evaluating the applicability of ultrasound for quantitative assessment of cartilage structure and properties. Bovine articular cartilage was investigated both in vitro and in situ using high frequency ultrasound. Cartilage samples were also tested mechanically in vitro to reveal relationships between acoustic and mechanical parameters of the tissue. The collagen organization and proteoglycan content of cartilage samples were mapped, using quantitative polarized light microscopy and digital densitometry, respectively, to reveal their effect on the acoustic properties of tissue. The high frequency pulse-echo ultrasound (20-30 MHz) technique proved to be sensitive in detecting the degeneration of the superficial collagen-rich cartilage zone. In addition, ultrasound was found to be a potential tool for measuring cartilage thickness. When the results from biomechanical indentation measurements and ultrasound measurements of normal and enzymatically degraded articular cartilage were combined, collagen or proteoglycan degradation in the tissue could be sensitively and specifically differentiated from each other. To conclude, high frequency ultrasound is a useful tool for evaluation of the quality of superficial articular cartilage as well as for the measurement of cartilage thickness. Therefore, ultrasound appears to be a valuable supplement to the mechanical measurements of articular cartilage stiffness.

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