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PubMed2002

Matrix metalloproteinases are involved in C-terminal and interglobular domain processing of cartilage aggrecan in late stage cartilage degradation.

Monoclonal antibody (MAb) technology was used to examine aggrecan metabolites and the role of aggrecanases and matrix metalloproteinases (MMPs) in proteolysis of the interglobular domain (IGD) and C-terminus of aggrecan. An in vitro model of progressive cartilage degradation characterized by early proteoglycan loss and late stage collagen catabolism was evaluated in conjunction with a broad-spectrum inhibitor of MMPs. We have for the first time demonstrated that IGD cleavage by MMPs occurs during this late stage cartilage degeneration, both as a primary event in association with glycosaminoglycan (GAG) release from the tissue and secondarily in trimming of aggrecanase-generated G1 metabolites. Additionally, we have shown that MMPs were responsible for C-terminal catabolism of aggrecan and generation of chondroitin sulfate (CS) deficient aggrecan monomers and that this aggrecan truncation occurred prior to detectable IGD cleavage by MMPs. The onset of this later stage MMP activity was also evident by the generation of MMP-specific link protein catabolites in this model culture system. Recombinant MMP-1, -3 and -13 were all capable of C-terminally truncating aggrecan with at least two cleavage sites N-terminal to the CS attachment domains of aggrecan. Through analysis of aggrecan metabolites in pathological synovial fluids from human, canine and equine sources, we have demonstrated the presence of aggrecan catabolites that appear to have resulted from similar C-terminal processing of aggrecan as that induced in our in vitro culture systems. Finally, by developing a new MAb recognizing a linear epitope in the IGD of aggrecan, we have identified two novel aggrecan metabolites generated by an as yet unidentified proteolytic event. Collectively, these results suggest that C-terminal processing of aggrecan by MMPs may contribute to the depletion of cartilage GAG that leads to loss of tissue function in aging and disease. Furthermore, analysis of aggrecan metabolites resulting from both C-terminal and IGD cleavage by MMPs may prove useful in monitoring different stages in the progression of cartilage degeneration.

Aggrecans↗

PubMed1999

Site-specific variation in femoral head cartilage composition in dogs at high and low risk for development of osteoarthritis: insights into cartilage degeneration.

OBJECTIVE: To determine which characteristics of cartilage lesion pathology are detected in dogs at high risk to develop osteoarthritis prior to diagnosis by standard radiographs or macroscopic cartilage abnormality on necropsy. METHODS: Fourteen disease-free dogs were assigned to risk groups based on hip distraction index. For seven dogs, three dimensional images of hip joints from computed tomography were available. At necropsy, ligamentum capitis femoris volumes were measured and articular cartilage was harvested and analyzed for percent water, swelling, glycosaminoglycan, and fibronectin. Comparisons were made with nine dogs with macroscopic cartilage lesions (OA group). RESULTS: Ligament volumes were greater in the high distraction index group (P=0.000). Water content was elevated in the lesion area in both low and high risk dogs (P=0.000); no additional increase was noted in the high risk group. Glycosaminoglycan content was slightly elevated in the surrounding area in both groups (P< 0.02) but loss was noted histologically in the lesion area of the high risk group. Fibronectin was increased in the lesion area and in the high risk group (P=0.000). The magnitude of this increase was greatest in the lesion area (P=0.000) in explants. Computed tomography indicated dorsal acetabular rim impingement on the lesion area in high risk dogs. CONCLUSIONS: Water content and swelling suggest matrix structure is weaker at the site of lesion predilection in all dogs regardless of risk status. Computed tomography imaging is consistent with site specific initiation of lesions by mechanical factors.

Animals↗

PubMed1999

Sulfation of chondroitin sulfate in human articular cartilage. The effect of age, topographical position, and zone of cartilage on tissue composition.

The chondroitin ABC lyase digestion products of normal human femoral condyle articular cartilage and of purified aggrecan were analyzed for their mono- and nonsulfated disaccharide composition. Changes in the total tissue chemistry were most pronounced during the period from birth to 20 years of age, when the -[GlcAbeta,3GalNAc6]- disaccharide content increased from approximately 50% to 85% of the total disaccharide content and there was a concomitant decrease in the content of the 4-sulfated disaccharide. In general, the disaccharide content of the deeper layers of immature cartilage were richer in the 4-sulfated residue than the upper regions of the tissue. As the tissue aged and decreased in thickness, the disaccharide composition became more evenly 6-sulfated. The newly synthesized chondroitin sulfate chains had a similar composition to the endogenous chains and also underwent the same age and zonal changes. The monoclonal antisera 3B3(+) and 2B6(+) were used to immunolocalize the unsaturated 6- and 4-sulfated residues generated at the reducing termini of the chondroitin sulfate chains by digestion with chondroitin ABC lyase, and these analyses indicated that the sulfation pattern at this position did not necessarily reflect the internal disaccharide composition of the chains. In summary, the sulfation pattern of chondroitin sulfate disaccharides from human normal articular cartilage varies with the age of the specimen, the position (topography) on the joint surface, and the zone of cartilage analyzed. Furthermore, these changes in composition are a consequence of both extracellular, post-translational processing of the core protein of aggrecan and changes in the sulfotransferase activity of the chondrocyte.

Adolescent↗

PubMed2000

Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation. Possible role in cartilage aging and the pathogenesis of osteoarthritis.

Reactive oxygen species (ROS) are implicated in both cartilage aging and the pathogenesis of osteoarthritis. We developed an in vitro model to study the role of chondrocyte-derived ROS in cartilage matrix protein degradation. Matrix proteins in cultured primary articular chondrocytes were labeled with [(3)H]proline, and the washed cell matrix was returned to a serum-free balanced salt solution. Exposure to hydrogen peroxide resulted in oxidative damage to the cell matrix as established by monitoring the release of labeled material into the medium. Calcium ionophore treatment of chondrocytes, in a dose-dependent manner, significantly enhanced the release of labeled matrix, suggesting a chondrocyte-dependent mechanism of matrix degradation. Antioxidant enzymes such as catalase or superoxide dismutase did not influence matrix release by the calcium ionophore-activated chondrocytes. However, vitamin E, at physiological concentrations, significantly diminished the release of labeled matrix by activated chondrocytes. The fact that vitamin E is a chain-breaking antioxidant indicates that the mechanism of matrix degradation and release is mediated by the lipid peroxidation process. Lipid peroxidation was measured in chondrocytes loaded with cis-parinaric acid. Both resting and activated cells showed constitutive and enhanced levels of lipid peroxidation activity, which were significantly reduced in the presence of vitamin E. In an immunoblot analysis, malondialdehyde and hydroxynonenal adducts were observed in chondrocyte-matrix extracts, and the amount of adducts increased with calcium ionophore treatment. Furthermore, vitamin E diminished aldehyde-protein adduct formation in activated extracts, which suggests that vitamin E has an antioxidant role in preventing protein oxidation. This study provides in vitro evidence linking chondrocyte lipid peroxidation to cartilage matrix protein (collagen) oxidation and degradation and suggests that vitamin E has a preventive role. These observations indicate that chondrocyte lipid peroxidation may have a role in the pathogenesis of cartilage aging and osteoarthritis.

Aldehydes↗

PubMed1958

Papain-induced changes in rabbit cartilage; alterations in the chemical structure of the cartilage matrix.

Some biochemical aspects of the collapse of the rabbit ears produced by the intravenous injection of papain have been studied. A marked depletion of chondromucoprotein (M.C.S.) and a reduction of the S(35) content of cartilage matrix were found to coincide with the gross and histologic changes in the cartilage. At the same time there was a marked increase in the amount of S(35) in the serum and an increase of S(35) and glucuronic acid excreted in the urine. Alteration in the composition of the M.C.S. remaining in the cartilage of the papain-injected animals was detected. The findings indicate that the collapse of the rabbit ears is due to loss of chondromucoprotein from cartilage and reduction of chondroitin sulfate in the chondromucoprotein that remains. All these changes were reversed in recovery.

Animals↗

PubMed1989

Gene regulation during cartilage differentiation: temporal and spatial expression of link protein and cartilage matrix protein in the developing limb.

The temporal and spatial expression of link protein and cartilage matrix protein genes was defined during chondrogenesis in the developing chick embryonic wing bud, using RNA in situ hybridization. For comparison, the expression of genes encoding type II collagen and cartilage proteoglycan core protein was also examined. Link protein transcripts are first detected at stage 25 of Hamburger and Hamilton, together with proteoglycan core protein transcripts. Type II collagen transcripts were first detected as early as stage 23 whereas cartilage matrix protein transcripts could not be detected before stage 26. The results of the study indicate that the temporal expression of the genes for cartilage matrix protein and type II collagen are independent of each other and also independent of that for link protein and proteoglycan core protein.

Animals↗

PubMed2001

Expression of caspase-3 and -9 relevant to cartilage destruction and chondrocyte apoptosis in human osteoarthritic cartilage.

To clarify the involvement of the caspase family in the pathway of NO-induced chondrocyte apoptosis, osteoarthritis (OA) cartilage obtained from 8 patients undergoing total hip arthroplasty were used for histopathological study. Cartilage samples taken from non-fibrillated areas of femoral head resected during surgery for femoral neck fracture were used for comparison. DNA fragmentation of chondrocytes was detected by the nick end-labeling (TUNEL) method. Apoptosis was further confirmed by transmission electron microscopy. The distributions of nitrotyrosine (NT), caspase-3, and -9 were examined immunohistochemically. The populations of apoptotic as well as NT-, caspase-3-, and -9-positive cells were quantified by counting the number of cells in the superficial, middle, and deep layers, respectively. The TUNEL-positive cells were observed primarily in superficial proliferating chondrocytes, clustering chondrocytes, and deep-layer chondrocytes of OA cartilage. Few positive cells were seen in the proliferating chondrocytes in the middle layer. Positive reactions for caspase-3 and -9 were observed in chondrocytes in similar areas. Histological OA grade showed significant correlations with the mean populations of apoptotic chondrocytes (% apoptosis) over the 3 areas. The populations of NT-positive cells (% NT) over the same areas also showed significant correlation with OA grade. Positivity for caspase-3 closely correlated with the OA grade, % apoptosis and %NT. It was concluded that caspase-3 and -9 could play a role in NO-induced chondrocyte apoptosis in OA cartilage.

Aged↗

PubMed1998

COMP (cartilage oligomeric matrix protein) is synthesized in ligament, tendon, meniscus, and articular cartilage.

The presence of cartilage oligomeric matrix protein (COMP) in extracts of ligament, tendon, meniscus, and canine articular cartilage was demonstrated by Western blot analysis using anti-dog COMP antibody. When the tissues were cultured in the presence of [35-S]methionine/cysteine, metabolically labeled COMP was purified from the culture media and from tissue extracts by DEAE-cellulose gel chromatography. SDS-Polyacrylamide gel electrophoresis (SDS-PAGE) followed by autoradiography and immunoblotting under reducing and non-reducing conditions revealed that COMP is synthesized by the cells of these connective tissues. Increased levels of COMP in samples of both synovial fluid and serum of patients with various joint diseases may not only be derived from cartilage but also from ligaments and tendons. COMP is not a highly tissue-specific cartilage molecule.

Animals↗

PubMed1997

Hepatocyte growth factor facilitates cartilage repair. Full thickness articular cartilage defect studied in rabbit knees.

Hepatocyte growth factor (HGF) is a multifunctional factor which promotes proliferation, motility and morphogenesis in epithelial cells. In addition, it has been found to play an important role in cartilage metabolism. To investigate articular cartilage repair using HGF in vivo, we injected HGF into rabbit knee joints, where 4 mm diameter osteochondral defects had been made, and observed the animals for 6 months. We found that HGF effectively repaired osteochondral defects. The repair process of the articular cartilage defects using HGF was shown to be much better than saline injection on all macroscopic and histologic examinations. Although the observation period in our study was short, HGF is one of the most promising candidates for repairing articular cartilage defects clinically.

Animals↗

PubMed1999

Repair of articular cartilage defects: part I. Basic Science of cartilage healing.

Articular cartilage injuries result in numerous clinical symptoms, such as pain and decreased functional levels. The limited reparative capabilities of hyaline cartilage results in the generation of repair tissue that lacks the structure and biomechanical properties of normal cartilage. Chondrocytes are unable to adequately proliferate, migrate, and synthesize high-quality repair tissue in response to blunt, superficial, or deep penetrating trauma. Extensive research has been conducted to understand the healing process and devise techniques that would enhance this response. Part I of this paper will discuss the basic science of cartilage repair. Part II, which will be published in the February issue, will present the treatment options.

Animals↗

PubMed2000

Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: matrix metalloproteinases-1 and -13 are involved in cartilage collagen breakdown.

Retinoic acid (RetA) and interleukin-1alpha (IL-1) together can induce a reproducible release of proteoglycan fragments from bovine nasal cartilage in culture. However, release of collagen fragments with either agent alone is often variable. In this study over 70% of the total collagen was released from bovine nasal cartilage in culture by day 14 when RetA and IL-1 were combined. This release was accompanied by the appearance of collagenolytic activity in the culture medium that cleaved collagen specifically at the (1/4)/(3/4) position. Tissue inhibitor of metalloproteinases (TIMP) activity was present at day 7 but low or absent in media from resorbing tissue at day 14. The breakdown of cartilage collagen could be prevented by the addition of BB-94, a specific metalloproteinase inhibitor. These results suggest that RetA promotes the early release of TIMP from the tissue and that IL-1 stimulates pro-collagenase secretion which, when activated, exceeds the local concentration of TIMP. Thus in the later stages of culture collagen destruction occurs. Both MMP-1 and MMP-13 were detected and appear to be involved in IL-1 + RetA induced bovine cartilage destruction. However, for the first time, we also present evidence to suggest that MMP-13 is the predominant collagenase in this system.

Animals↗

PubMed2003

[Alteration of the expression of cartilage matrix molecule in the cartilage by the chondrocytes from rabbit temporomandibular joint with experimental osteoarthritis and its response to interleukin-1 beta].

OBJECTIVE: To study the effect of interleukin-1 (IL-1 beta) on the metabolism of osteoarthritic and normal mature condylar chondrocytes in temporomandibular joints, and investigate the role of IL-1 beta in the pathogenesis of temporomandibular joint osteoarthritis. METHODS: The primary generation of osteoarthritic and normal condylar chondrocytes cultured in the monolayer condition was treated with 20 micrograms.L-1 recombined human interleukin-1 beta (rhIL-1 beta), and then collected to be detected with RT-PCR method for the cellular metabolism including mRNA expression of type II collagen, aggrecan, collagenase, insulin-like growth factor 1 (IGF-1), and transforming growth factor beta 1 (TGF beta 1). RESULTS: The normal mature condylar chondrocytes showed the obviously decreased mRNA expression of type II collagen and aggrecan after the intervention of exogenous IL-1 beta, but less influence could be found for the collagenase expression. The osteoarthritic condylar chondrocytes exhibited the decreased mRNA expression of type II collagen and collagenase under the effect of IL-1 beta, while the cellular mRNA expression of aggrecan didn't change obviously. The intervention of exogenous IL-1 beta didn't show an obvious influence on the cellular expression of endogenous growth factors such as IGF-1 or TGF-beta 1 for both the normal and osteoarthritic condylar chondrocytes cultured in vitro. CONCLUSION: IL-1 beta could not only disturb the expression of cartilage matrix molecules by the normal condylar chondrocytes, which lead to the lesion of condylar cartilage, but also worsen the abnormal cartilage matrix environment within the osteoarthritic condylar cartilage.

Animals↗

PubMedDate not supplied

New cell-based technologies in bone and cartilage tissue engineering. II. Cartilage regeneration.

A tissue engineering, cell-based therapeutic approach could be essential for extensive bone or cartilage reconstruction. This article is divided in two chapters and describes new cell-based surgical techniques for cartilage and bone reconstruction. The second part of the article, regarding cartilage repair, describes a new arthroscopic surgical technique for tissue engineered cartilage grafting. A 3-dimensional hyaluronic acid support is used for autologous chondrocyte culturing. The technique reduces morbidity of classic autologous implant avoiding open surgery and periosteal flap use. With this technique is possible to reduce the patient morbidity, time and cost of surgery.

Adolescent↗

PubMed2004

[Study on the metabolism of cartilage matrix by the chondrocytes in osteoarthritic condylar cartilage].

OBJECTIVE: To study the characteristics of cellular metabolism of mandibular condylar chondrocytes in repairing state of osteoarthrosis and investigate its role in the pathogenesis of the disease. METHODS: Temporomandibular joint osteoarthrosis model of rabbits was created by the partial resection of joint disc and confirmed with histological diagnosis. The chondrocytes were harvested from osteoarthritic condylar cartilage in the repairing state and cultured in vitro under the monolayer culture condition. The cellular expression of cartilaginous matrix protein, collagenase and growth factors between the osteoarthritic chondrocytes and the normal controls were measured with RT-PCR technique to outline the basic feature of the osteoarthritic cells. RESULTS: The cultured cells were confirmed as chondrocytes with their ability of expression of collagen type II and Aggrecan. In the reactive repairing state of osteoarthrosis, the chondrocytes showed the imbalance of expression of ECM proteins, and increased expression of collagenase and endogenous growth factors such as IGF-1 and TGF-beta1. CONCLUSIONS: This study found the active anabolism of the chondrocytes within the osteoarthritic condylar cartilage and the imbalance synthesis of cartilage matrix. These repairing attempts by the osteoarthritic chondrocytes may be impossible to restore the primary homeostasis within the condylar cartilage.

Animals↗

PubMed1992

Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage.

An Mr = 524,000 oligomeric protein was isolated from bovine cartilage and designated COMP (Cartilage Oligomeric Matrix Protein). The protein is composed of disulfide-bonded subunits with an apparent Mr of 100,000 each. It is markedly anionic, probably due to its high contents of aspartic acid and glutamic acid, as well as to its substitution with negatively charged carbohydrates. COMP was found in all cartilages analyzed, but could not be detected in other tissues by enzyme-linked immunosorbent assay of guanidine HCl extracts. Within a given cartilage, COMP shows a preferential localization to the territorial matrix surrounding the chondrocytes.

Amino Acids↗

PubMed1987

[Detection of low molecular weight trypsin inhibitors in small samples of cartilage, cartilage extracts and synovial fluid by gel diffusion].

The radial diffusion assay is a very useful method for detection of low amounts of proteinase inhibitors in biological materials. The determination of low molecular weight (LMW) inhibitors in the presence of high molecular weight inhibitors is possible by the combination of radial diffusion and ultrafiltration. Using this method LMW trypsin inhibitors could be demonstrated in human articular cartilage, but not in human synovial fluid. In cow, pig and sheep a LMW trypsin inhibitor could be found in both the articular cartilage and in the synovial fluid. On the other hand, a LMW trypsin inhibitor could not be found neither in the canine cartilage nor in the canine synovial fluid. The method allows also the direct determination of LMW trypsin inhibitors in cartilage extracts in the presence of 4 M guanidinium hydrochloride or 6 M urea. Therefore, the method is recommended for direct determination of LMW inhibitors by column chromatographic separations of inhibitors.

Animals↗

PubMedDate not supplied

[Cellular aspects of the aging of articular cartilage. I. Condylar cartilage with a normal surface sampled from normal knees].

The authors studied the cellular density of articular cartilage taken from the femoral condyles of 77 autopsy subjects at Hôpital Lariboisière in Paris. This study showed a decrease in the cellular density (number of chondrocytes per mm2) going from the superficial zone towards the calcified zone of the cartilage in all layers, as a function of the age of the subjects. The decrease in cellular density is in the order of about 50% of the total chondrocyte number when subjects younger than 40 are compared with those older than 80. The demonstration of a regular increase in the number of empty lacunae per mm2 with the age of the subjects, i.e. lacunae without chondrocytes, suggest that the cause of this decrease in cellular density of the cartilage with age could be a physiological necrosis due to "exhaustion" of the chondrocytes. The metabolic activity of the chondrocytes may also decrease with age, as suggested by the increasing proportion of alcianophobic cells, cells which are weakly or not at all labeled by radioactive sulfates which indicate the sites of biosynthesis of proteoglycans. These cellular modifications could play a role of senile fibrillation of articular cartilage and in arthrosis.

Adult↗

PubMed1983

[Tympanoplasty with tragus cartilage transplant: "cartilage cover plasty"].

Transplants composed in three layers of tragus cartilage and perichondrium are ideally suited for eardrum transplants. They are easily prepared, well-nourished, stable and withstand retraction tendencies due to negative middle ear pressure. One overlapping perichondrium layer forms, so to speak, the live rail for the eardrum epithelium. To this perichondrium layer the cartilage disk is safely attached. The cartilage disk attached to its outer perichondrium layer--also covered by the perichondrium towards the middle ear--is thus fastened like a circular tape in the eardrum frame similar to the foot plate of the stapes. The eardrum seal is safe; in 87 operations we observed only one case of the edge coming away which was due to the transplant being too small. This type of transplant has proved its worth especially when reconstructing the ossicle chain with column protheses (TORP, PORP). The excellent hearing results may be explained by the optimum transformation of air pressure from the large cartilage via the medium-sized prosthesis screen, which is attached to the surface, to the small foot plate of the stapes. The "tragus" transplant can also be used in case of a Type III interposition of incus.

Cartilage↗