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PubMed1996

Altered aggrecan synthesis correlates with cell and nucleus structure in statically compressed cartilage.

Previous studies have shown that static equilibrium compression of cartilage tissue in vivo and in vitro decreases chondrocyte synthesis of aggrecan molecules. In order to identify mechanisms of cellular response to loading, we have investigated alterations in cell and nucleus structure and the accompanying changes in the synthesis of aggrecan in statically compressed cartilage explants. Using glutaraldehyde fixation and quantitative autoradiography of compressed and radiolabeled cartilage disks we spatially localized newly synthesized aggrecan. Using stereological tools to analyze these same specimens we estimated the cell and nucleus volume, surface area and directional radii. We found that aggrecan synthesis was reduced overall in compressed tissue disks. However, the compression induced a spatial (radial) inhomogeneity in aggrecan synthesis which was not present in uncompressed disks. This spatial inhomogeneity appeared to be directly related to mechanical boundary conditions and the manner in which the load was applied and, therefore, may represent a spatially specific functional adaptation to mechanical loading. Coincident with reduced aggrecan synthesis, we observed reductions in cell and nucleus volume and radii in the direction of compression which were in approximate proportion to the reduction in tissue thickness. Cell and nucleus dimensions perpendicular to the direction of compression did not change significantly. Therefore the observed deformation of the cell and nucleus in statically compressed cartilage approximately followed the dimensional changes imposed on external specimen surfaces. The strong correlation observed between local changes in aggrecan synthesis and alterations in cell and nucleus structure also lend support to certain hypotheses regarding the intracellular signal transduction pathways that may be important in the biosynthetic response of chondrocytes to mechanical loading.

Aggrecans↗
PubMed2006

[Protective effect of selenium against T-2 toxin-induced inhibition of chondrocyte aggrecan and collagen II synthesis].

OBJECTIVE: To study the inhibitory effect of T-2 toxin on the expression of aggrecan and collagen II in chondrocytes and the protection of selenium against this effect. METHODS: Human chondrocytes cultured in vitro were treated with T-2 toxin at different concentrations for varied time periods (1-5 days), and the cell viability was measured by MTT assay. Aggrecan expression was detected by toluidine blue staining and collagen II expression by immunostaining using monoclonal antibody of collagen. Aggrecan and collagen II mRNA expressions were measured by semiquantitative RT-PCR. RESULTS: T-2 toxin dose- and time-dependently affected chondrocyte viability within the concentration range of 0.001-2 mg/L, the prolonged treatment time further enhanced the dose dependence of the inhibitory effect. T-2 toxin lowered aggrecan and collagen II synthesis in the chondrocytes and reduced their mRNA expressions. Selenium could partly attenuate the inhibitory effects of T-2 toxin on aggrecan mRNA expression, but showed no such effect against T-2-induced collagen II expression. CONCLUSION: T-2 toxin can obviously inhibit aggrecan and collagen II synthesis in human chondrocytes, and selenium can partly antagonize the inhibitory effects of T-2 toxin on aggrecan.

Aggrecans↗
PubMed1993

Expression of alternatively spliced epidermal growth factor-like domains in aggrecans of different species. Evidence for a novel module.

The carboxyl-terminal globular domain of human aggrecan has been shown previously to contain an alternatively spliced epidermal growth factor (EGF)-like module. We have used reverse transcription/polymerase chain reactions on cartilage-derived RNAs to investigate the heterogeneity in the EGF-like domain content of aggrecans from five species (mouse, rat, dog, bovine, and human). A novel alternatively spliced EGF-like module was detected in human aggrecan, establishing the presence of two of these domains. Highly homologous domains are present in aggrecans of other species, and the expression of these modules is identical (4-8%). They share significant homology with EGF-like domains of differentiation proteins and coagulation factors and have a putative calcium binding site. In contrast to this novel domain (EGF2), the previously described EGF-like module (EGF1) is expressed at a high level exclusively in human aggrecan. The expression of the two EGF-like domains in human aggrecan appears to be independent. Although the function of these domains is not understood, the uniform expression of the EGF2 domain may indicate a general role of this aggrecan module, while the expression of the EGF1 domain may reflect species specificity.

Aggrecans↗
PubMed1996

Aggrecan: A Target Molecule of Autoimmune Reactions.

Aggrecan in cartilage forms aggregates with hyaluronan and link protein, embedded in a collagen network. It accounts for the compressive stiffness and resilience of the hyaline cartilage. Many forms of inflammatory arthritis were shown to be accompanied with aggrecan degradation and loss from the cartilage. The loss of this major component of cartilage renders the tissue more vulnerable when exposed to abrasive forces. Therefore, aggrecan degradation may significantly contribute to cartilage destruction in arthritis. Furthermore, fragments of degraded aggrecan are released during joint inflammation. Thus, molecules of an avascular, immune-privileged tissue (hyaline cartilage) may become accessible to the cells of the immune system. Similarly, there is a "leakage" of aggrecan fragments from cartilage during aging and after joint injury, which may also lead to autosensibilisation. Autoimmune reactivity to aggrecan can be detected in human joint diseases, as well as in animal models of arthritis. The epitopes involved in these processes are currently being identified. Recent data from work with mice suggest a strong immune response focused to the N-terminal G1 domain of aggrecan that leads to arthritis and spondylitis.

Journal Article↗
PubMed1999

Distinct spatial and temporal distributions of aggrecan and versican in the embryonic chick heart.

Although chondroitin sulfate proteoglycans (CSPGs) are major components of the embryonic extracellular matrix, little attention has been paid to specific CSPGs in early heart development, in part because appropriate antibodies were not available. Therefore we prepared specific polyclonal antibodies against chicken aggrecan, versican, neurocan, and phosphacan. Western blotting and immunohistochemical studies revealed the presence of aggrecan and versican in stages 12-21 chicken embryo hearts in distinctive spatial and temporal patterns. Because this is the first demonstration of aggrecan in heart tissue, we further used RT-PCR to confirm that aggrecan is expressed in the heart and in situ hybridization to confirm the pattern of expression determined using antibodies. Versican is found in the myocardium and the myocardial basement membrane. In contrast, aggrecan is specifically colocalized with several groups of migrating cells including endocardial cushion tissue cells, epicardial cells, a mesenchymal cell population in the outflow tract that may be of neural crest origin, and a mesenchymal cell population in the inflow tract. The combined observations indicate that versican and aggrecan are expressed in unique patterns and suggest that they play very different roles in development.

Aggrecans↗
PubMed1999

The early molecular natural history of experimental osteoarthritis. I. Progressive discoordinate expression of aggrecan and type II procollagen messenger RNA in the articular cartilage of adult animals.

OBJECTIVE: To quantify changes in the chondrocyte metabolism of aggrecan core protein and type II procollagen messenger RNA (mRNA) during the early and middle phases of experimental osteoarthritis (OA) in animals. METHODS: Experimental OA was induced by transecting the cranial cruciate ligament of the stifle joint in adult animals; articular cartilage was harvested and analyzed after 4, 10, and 32 weeks. RESULTS: Northern blot analysis revealed no change in aggrecan mRNA 4 weeks after surgery compared with aggrecan mRNA in the unoperated contralateral control joints; aggrecan mRNA levels became significantly elevated by 10 and 32 weeks after surgery. In OA cartilage, type II procollagen mRNA was dramatically and progressively elevated at all times after surgery. The relative increases in type II procollagen mRNA exceeded the relative increases in aggrecan mRNA at all times after surgery, and these differences increased progressively over time. Articular chondrocytes became activated globally (total RNA increases) and specifically (mRNA increase) early after joint injury and remained activated throughout the early and middle phases of this experimental OA. CONCLUSION: The early natural history of experimental OA is characterized by a progressive imbalance in the mRNA expression of aggrecan and type II procollagen in articular chondrocytes. These results suggest that the stimuli for the transcription of these 2 genes are fundamentally different in this animal model.

Aggrecans↗
PubMed2000

Osteogenic protein 1 stimulates cells-associated matrix assembly by normal human articular chondrocytes: up-regulation of hyaluronan synthase, CD44, and aggrecan.

OBJECTIVE: To determine the effects of osteogenic protein 1 (OP-1) on hyaluronan (HA), CD44, and aggrecan biosynthesis as well as the contribution of these molecules in promoting matrix assembly by human articular chondrocytes. METHODS: Normal human chondrocytes were cultured with or without OP-1 treatment. Changes in the relative expression of messenger RNA (mRNA) for HA synthases 2 and 3 (HAS-2 and HAS-3), CD44, and aggrecan were determined by competitive quantitative reverse transcriptase-polymerase chain reaction. Accumulation of HA was characterized by indirect staining, CD44 by flow cytometry, and aggrecan biosynthesis by 35SO4 incorporation. RESULTS: OP-1 stimulated the expression of HAS-2, CD44, and aggrecan mRNA in a time-dependent manner, resulting in increased expression of HA, CD44, and aggrecan. Prominent increases in HA-rich cell-associated matrices were also observed. CONCLUSION: OP-1 stimulates not only the synthesis of matrix macromolecules such as aggrecan, but also the synthesis of other molecules required for matrix retention, namely, HA and CD44.

Aggrecans↗
PubMed1993

The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis.

OBJECTIVE: To determine the proteolytic fragmentation patterns and N-terminal sequence of aggrecan fragments in human synovial fluid from patients with inflammatory arthritides, joint injury, or osteoarthritis (OA). METHODS: Knee synovial fluid was obtained from patients with joint injury, OA, acute pyrophosphate arthritis (pseudogout), reactive arthritis, psoriatic arthritis, or juvenile rheumatoid arthritis. Chondroitin sulfate-substituted aggrecan fragments present in the fluid were purified by cesium chloride gradient centrifugation and enzymatically deglycosylated. Core protein species were determined by N-terminal analysis and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with electroblotting and detection with monoclonal antibody 3B3. RESULTS: Samples from patients with joint injury, OA, and inflammatory joint disease all showed a similar 3-band pattern, with core sizes of approximately 200 kd, 170 kd, and 135 kd. In all samples, diffuse immunoreactive products were also seen, with an apparent size of > 250 kd. N-terminal analysis of core preparations of all samples showed a consistent single predominant sequence, beginning at alanine 374 of the human aggrecan core protein. CONCLUSION: The aggrecan fragments present in joint fluids from patients with various inflammatory arthritides, joint injury, or OA result from a predominant cleavage of the human aggrecan core protein at the glutamate 373-alanine 374 bond within the interglobular domain, between the G1 and G2 domains. The consistent pattern of fragments seen on SDS-PAGE and the single predominant N-terminal sequence suggest a common degradative mechanism of aggrecan in these different joint conditions. The identity of the proteolytic agent (aggrecanase), however, remains unknown. These results appear to have important implications with regard to the development of therapies to protect cartilage from degradation in patients with joint disease.

Adolescent↗
PubMed2003

Developmental expression of the HNK-1 carbohydrate epitope on aggrecan during chondrogenesis.

Previously, we showed that the HNK-1 carbohydrate epitope is expressed on aggrecan synthesized in the notochord but not in mature cartilage. In the present study, we demonstrate that in immature cartilage (embryonic day 6) the HNK-1 epitope is also expressed predominantly on aggrecan proteoglycan molecules. This finding was verified by using an aggrecan-deficient mutant, the nanomelic chick, which lacks HNK-1 immunostaining in the extracellular matrix of dividing and hypertrophic chondrocytes as late as embryonic day 12. By using both biochemical and immunologic approaches, the initially prominent expression of the HNK-1 epitope is down-regulated as development of limb and vertebral cartilage proceeds, so that by embryonic day 14 no HNK-1 is detectable. Localization changes with development and the HNK-1-aggrecan matrix becomes restricted to dividing and hypertrophic chondrocytes and is particularly concentrated in the intraterritorial matrix. Concomitant with the temporal and spatial decreases in HNK-1, there is a significant increase in keratan-sulfate content and the aggrecan-borne HNK-1 epitope is closely associated with proteolytic peptides that contain keratan sulfate chains, rather than chondroitin sulfate chains or carbohydrate-free domains. Lastly, the diminution in HNK-1 expression is consistent with a reduction in mRNA transcripts specific for at least one of the key enzymes in HNK-1 oligosaccharide biosynthesis, the HNK-1 sulfotransferase. These findings indicate that the HNK-1 carbohydrate may be a common modifier of several proteoglycans (such as aggrecan) that are usually expressed early in development, and that HNK-1 addition to these molecules may be regulated by tissue- and temporal-specific expression of requisite sulfotransferases and glycosyltransferases.

Aggrecans↗
PubMed2001

Enzymes active in the areas undergoing cartilage resorption during the development of the secondary ossification center in the tibiae of rats ages 0-21 days: I. Two groups of proteinases cleave the core protein of aggrecan.

The formation of a secondary ossification center in the cartilaginous epiphysis of long bones requires the excavation of canals and marrow space and, therefore, the resorption of cartilage. On the assumption that its resorption requires the lysis of the major cartilage component aggrecan, it was noted that the core protein may be cleaved in vitro by proteinases from two subfamilies: matrix metalloproteinases (MMPs) and aggrecanases. Such cleavage results in aggrecan being replaced by a fragment of itself referred to as a "G1-fragment." To find out if this cleavage occurs in the developing epiphysis of the rat tibia, the approach has been to localize the G1 fragments. For this purpose two neoepitope antisera were applied, one capable of recognizing the MMP-generated G1-fragment that bears the C-terminus ...FVDIPEN341 and the other capable of recognizing the aggrecanase-generated G1-fragment that carries the C-terminus ...NITEGE373. With the aid of these antisera, we report here that aggrecan cleavage is localized to newly developed sites of erosion. Thus, at 6 days of age, canals allowing the entry of capillaries are dug out from the surface of the epiphysis in a radial direction (stage I), whereas immunostaining indicative of aggrecan cleavage by MMPs appears at the blind end of each canal. The next day, the canal blind ends fuse to create a marrow space in the epiphysis (stage II), whereas immunostaining produced by MMPs occurs along the walls of this space. By 9 days, clusters of hypertrophic chondrocytes are scattered along the marrow space wall to initiate the formation of the secondary ossification center (stage III), where the resorption sites are unreactive to either antiserum. From the 9th to the 21st day, the center keeps on enlarging and, as the distal wall of the marrow space recedes, it is intensely immunostained with both antisera indicating that both MMPs and aggrecanases are involved in this resorption. We conclude, that both enzyme subfamilies contribute to the lysis of aggrecan. However, the results suggest that the respective subfamilies target different sites and even stages of development in the tissue, suggesting some diversity in the mode of aggrecan lysis during the excavation of a secondary ossification center.

Aggrecans↗
PubMed2003

Increases in cytosolic calcium, but not fluid flow, affect aggrecan mRNA levels in articular chondrocytes.

Fluctuations in intracellular free calcium concentration ([Ca2+]i) is thought to be one mechanism by which cells transduce mechanical signals into biological responses. Primary cultures of bovine articular chondrocytes (BAC) respond to oscillating fluid flow with a transient rise in [Ca2+]i. However, specific down-stream effects of [Ca2+]i on gene expression and phenotype in BAC remain to be defined. The present work was designed to determine whether [Ca2+]i mobilization regulates aggrecan mRNA levels. [Ca2+]i was transiently elevated by exposing BAC to the [Ca2+]-specific ionophore, ionomycin. The results show that ionomycin increases [Ca2+]i in a dose-dependent fashion. Semi-quantitative real time (RT)-PCR was used to study the effects of increased [Ca2+]i on steady state levels of aggrecan mRNA. Four hours after a brief exposure to 1.5 microM ionomycin, BAC displayed a nearly four-fold decrease in aggrecan mRNA levels compared to control cells. This effect of ionomycin on aggrecan mRNA was no longer evident 6 or 10 h later. Despite previous observations that oscillating fluid flow elicits increased [Ca2+]i in BAC, it did not affect aggrecan mRNA levels. Taken together, these data suggest that ionomycin-induced [Ca2+]i fluctuations regulate aggrecan mRNA levels, but that flow induced [Ca2+]i fluctuations do not.

Aggrecans↗
PubMed1997

Complete coding sequence of bovine aggrecan: comparative structural analysis.

The previously available sequence for bovine aggrecan included only the KS domain, the C-terminal portion of the CS-2 domain, and the entire CS-3 and G3 domains. We have isolated cDNA clones for previously uncharacterized portions of the bovine aggrecan sequence, and, when we combined them with previously published incomplete sequences, have obtained a complete sequence for the entire core protein. The bovine aggrecan sequence, which is a composite of new sequence data and previously published incomplete sequences, is 2327 residues in length. Although there is significant conservation of G1, G2, and G3 globular domains between species, there are differences in the length of the interglobular domain, in the number of KS domain hexapeptide repeats and CS domain repeats, and in alternative splicing within the G3 domain. The bovine aggrecan KS domain contains 24 repeats of a hexapeptide motif. The largely uncharacterized CS-1 domain of bovine aggrecan was found to contain 27 variable repeats of a 21-residue consensus sequence. A notable feature of the bovine CS-1 domain is in the distribution of single Ser-Gly dipeptides, the majority of which are separated by 7 or 8 amino acids, compared to the human, where discrete pairs of Ser-Gly dipeptides are separated by 13 amino acids. The CS-2 domain contains a total of six "homology domains" with 4 complete and 2 partial approximately 100-residue repeats. Each "homology domain" contains a "nodal" region with few sites for CS chain addition that is highly conserved between species, suggesting a possible role in aggrecan biosynthesis or catabolism.

Aggrecans↗
PubMed1999

Stimulation of aggrecan synthesis in cartilage explants by cyclic loading is localized to regions of high interstitial fluid flow.

Chondrogenesis in cartilage development and repair and cartilage degeneration in arthritis can be regulated by mechanical-load-induced physical factors such as tissue deformation, interstitial fluid flow and pressure, and electrical fields or streaming potentials. Previous animal and tissue explant studies have shown that time-varying dynamic tissue loading can increase the synthesis and deposition of matrix molecules in an amplitude-, frequency-, and spatially dependent manner. To provide information on the cell-level physical factors which may stimulate chondrocytes to increase production and export of aggrecan, the main proteoglycan component of the cartilage matrix, we characterized local changes in aggrecan synthesis within cyclically loaded tissue explant disks and compared those changes to values of predicted local physical factors. Aggrecan synthesis following a 23-h compression/radiolabel protocol was measured with a spatial resolution of approximately 0.1 mm across the 1.5-mm radius of explanted disks using a quantitative autoradiography method. A uniform stimulation of aggrecan synthesis was observed at an intermediate frequency of 0.01 Hz, while, at a higher frequency of 0.1 Hz, stimulation was only seen at peripheral radial positions. Profiles of radial solid matrix deformation and interstitial fluid pressure and velocity predicted to be occurring across the radius of the disk during sinusoidal loading were estimated using a composite poroelastic model. Tissue regions experiencing high interstitial fluid velocities corresponded to those displaying increased aggrecan synthesis. These results reinforce the role of load-induced flow of interstitial fluid in the stimulation of aggrecan production during dynamic loading of cartilage.

Aggrecans↗
PubMed1994

Complete coding sequence, deduced primary structure, chromosomal localization, and structural analysis of murine aggrecan.

We have isolated and sequenced overlapping cDNA clones encoding the entire core protein of aggrecan (the large aggregating chondroitin sulfate/keratan sulfate proteoglycan of cartilage) from three chondrocyte cDNA libraries of BALB/c mice and localized the aggrecan gene in mouse chromosome 7. We determined 7386 bp of the cDNA sequence, including 132 and 854 nucleotides of 5' and 3' untranslated regions, respectively. The core protein precursor is 2132 amino acids long (M(r) 222,008), including a 19-residue secretory signal peptide. The overall amino acid sequence of the mouse aggrecan shows 91.6% identity to rat and 72.5% to human aggrecan. Comparison of the amino acid sequences of various domains and subdomain structures of mouse aggrecan to known sequences of other species and related proteins (versican, neurocan, link protein, and lymphocyte homing receptor CD44) revealed high levels of identity of the G1, G2, and G3 globular domains and relatively less conserved structures in the interglobular and glycosaminoglycan-attachment regions. Epidermal growth factor (EGF)-like module was detected in only a minor fraction of aggrecan clones, while the complement regulatory protein (CRP)-like domain was regularly expressed in all samples.

Aggrecans↗
PubMed1992

Monoclonal antibodies directed against epitopes within the core protein structure of the large aggregating proteoglycan (aggrecan) from the swarm rat chondrosarcoma.

The core protein of the large hyaline cartilage proteoglycan, aggrecan, is composed of six distinct domains: globular 1 (G1), interglobular, globular 2 (G2), keratan sulfate attachment, chondroitin sulfate (CS) attachment, and globular 3 (G3). Monoclonal antibodies that recognize epitopes in these domains were raised against Swarm rat chondrosarcoma aggrecan that was either denatured through reduction and alkylation or partially deglycosylated through chondroitinase ABC digestion or alkali elimination, the latter with or without sulfite addition. Monoclonal antibodies were further characterized for reactivity to purified aggrecan substructures including rat chondrosarcoma G1 and CS attachment domains, a recombinant rat chondrosarcoma G3 domain fusion protein, bovine articular cartilage G2 domain, and rat chondrosarcoma link protein (LP). Biochemical characterization of the specificities of these monoclonal antibodies indicated that one (1C6) recognized an epitope shared by both the G1 and the G2 domains; one (5C4) recognized an epitope shared by both LP and the G1 domain; one (7D1) recognized an epitope shared by both the G1 and the CS attachment domains; two (14A1 and 15B2) recognized epitopes in the CS attachment domain; one (14B4) recognized an epitope in the G3 domain; and one (13D1) recognized a ubiquitous epitope shared by the G1, G2, G3, and CS attachment domains of aggrecan and also LP. Collectively the specificities of these antibodies confirm the occurrence of multiple repeated epitopes (both carbohydrate and protein in nature) throughout the different domain structures of aggrecan. These antibodies have been proven to be useful for identifying aggrecan-like molecules in several connective tissues other than cartilage.

Aggrecans↗
PubMed1992

Variability in the G3 domain content of bovine aggrecan from cartilage extracts and chondrocyte cultures.

The content of the globular domains G1, G2 and G3 on the core protein of high-density (A1D1) aggrecan isolated from newborn and mature bovine cartilage and from cultures of bovine chondrocytes was examined. Quantitation based on the 220 nm absorbance of tryptic marker peptides from each domain isolated by reversed-phase HPLC showed that while the content of G1 and G2 was essentially the same for all samples, the content of G3 varied markedly. The molar yield of G3 and G1 marker peptides indicated that approximately 55% of the G1-bearing aggrecan from immature cartilage carried the G3 domain, while for mature cartilage this figure was markedly reduced, at about 35%. Aggrecan prepared from the cell layer matrix of calf chondrocyte cultures had an apparent G3 content similar to newborn cartilage (55%), whereas aggrecan prepared from the medium of these cultures had a markedly higher G3 content, at about 80%. The high content of G3 in cell medium samples compared to cartilage extracts was supported by electron microscopic analysis of A1D1 preparations. The G3 content of the two subpopulations of aggrecan present in mature cartilage and separable by flat bed agarose gel electrophoresis was also determined at about 45% (Band I) and 20% (Band II) respectively. These results are discussed in terms of the likely origin of the marked variability in the G3 domain content of aggrecan.

Aggrecans↗
PubMed1994

Analysis of aggrecan and tenascin gene expression in mouse skeletal tissues by northern and in situ hybridization using species specific cDNA probes.

Cartilage matrix is an interacting multicomponent system of collagen fibrils, fibril-associated small proteoglycans, and large proteoglycans and glycoproteins entrapped within the fibrillar network. In order to better understand the relationships between these different components we have constructed short cDNA clones for detection of mRNAs for two major noncollagenous macromolecules of cartilage matrix, aggrecan and tenascin. We subsequently determined their corresponding mRNA levels by Northern analysis in a panel of total RNAs isolated from several newborn mouse tissues. The expression of aggrecan was strictly restricted to cartilages while tenascin mRNA was present at variable levels in most of the tissues studied. The cDNA clones were also used to identify the cells responsible for aggrecan and tenascin production in newborn mouse tissues by in situ hybridization. With this technique aggrecan mRNA was detected in chondrocytes throughout the developing skeleton in a pattern very similar but not identical to those of type II and IX collagen mRNAs. In the newborn mouse skeleton tenascin and aggrecan mRNAs were expressed essentially in a mutually exclusive manner, tenascin transcripts being present in osteoblasts, periosteal and perichondrial cells, and in cells at articular surfaces. None of these cells expressed the cartilage specific collagen or aggrecan genes. The results further suggest different patterns of gene expression in chondrocytes based on their location in the different cartilages.

Aggrecans↗
PubMed1994

Length variation in the keratan sulfate domain of mammalian aggrecan.

The keratan sulfate domain of aggrecan consists of a series of tandemly repeating hexapeptides which have the consensus sequence Glu-Glu/Lys-Pro-Phe-Pro-Ser, where the serine side-chains presumably provide sites for the attachment of keratan sulfate (KS) chains. The number of hexapeptide repeats varies between species, ranging from four in rat (Doege et al., 1987) and mouse (Walcz et al., 1992) to 13 in human (Doege et al., 1991) and 23 in bovine aggrecan (Antonsson et al., 1989). Chicken aggrecan (Chandrasekaran and Tanzer, 1992) does not contain a KS domain with a recognizable hexapeptide motif. The extent of this variation among mammalian and avian species is not known, and there is currently no explanation to predict how differences in the size of the KS domain would affect aggrecan function. We used polymerase chain reaction (PCR) to amplify the portion of the human, canine and porcine aggrecan gene that codes for the KS domain. We sequenced the amplified products in each case. Human aggrecan, with 13 hexapeptide repeats (Doege et al., 1987), was used as reference and found to be essentially identical to published data. The canine and porcine KS domains consisted of six and ten hexapeptide repeats respectively. The same PCR protocol was used to amplify the KS domain from genomic DNA of eight other mammalian species. Comparison of the size of these amplified products, as determined by agarose gel electrophoresis, with those for which sequence data are available allowed us to estimate the number of repeats in the KS domain. In almost half the species examined, the KS domain consisted of 13 hexapeptide repeats.

Aggrecans↗