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Biomedical subjects

D Heinegard

Publications and source records attributed to D Heinegard.

10 recordsLinked to original sources
PubMed2001

Identification and characterization of asporin. a novel member of the leucine-rich repeat protein family closely related to decorin and biglycan.

Asporin, a novel member of the leucine-rich repeat family of proteins, was partially purified from human articular cartilage and meniscus. Cloning of human and mouse asporin cDNAs revealed that the protein is closely related to decorin and biglycan. It contains a putative propeptide, 4 amino-terminal cysteines, 10 leucine-rich repeats, and 2 C-terminal cysteines. In contrast to decorin and biglycan, asporin is not a proteoglycan. Instead, asporin contains a unique stretch of aspartic acid residues in its amino-terminal region. A polymorphism was identified in that the number of consecutive aspartate residues varied from 11 to 15. The 8 exons of the human asporin gene span 26 kilobases on chromosome 9q31.1-32, and the putative promoter region lacks TATA consensus sequences. The asporin mRNA is expressed in a variety of human tissues with higher levels in osteoarthritic articular cartilage, aorta, uterus, heart, and liver. The deduced amino acid sequence of asporin was confirmed by mass spectrometry of the isolated protein resulting in 84% sequence coverage. The protein contains an N-glycosylation site at Asn(281) with a heterogeneous oligosaccharide structure and a potential O-glycosylation site at Ser(54). The name asporin reflects the aspartate-rich amino terminus and the overall similarity to decorin.

Adult↗
PubMed2000

The amino-terminal part of PRELP binds to heparin and heparan sulfate.

PRELP (proline, arginine-rich end leucine-rich repeat protein) is an extracellular matrix leucine-rich repeat protein. The amino-terminal region of PRELP differs from that of other leucine-rich repeat proteins in containing a high number of proline and arginine residues. The clustered proline and basic residues are conserved in rat, bovine, and human PRELP. Although the function of PRELP is not yet known, the clustered arginine residues suggest a heparan sulfate/heparin-binding capacity. We show here that PRELP indeed binds heparin and heparan sulfate. Truncated PRELP without the amino-terminal region does not bind heparin. The dissociation constant for the interaction of PRELP with heparin was determined by an in solution binding assay and by surface plasmon resonance analysis to be in the range of 10-30 nm. A 6-mer heparin oligosaccharide was the smallest size showing binding to PRELP. The binding increased with increasing length up to an 18-mer and depended on the degree of sulfation of heparin as well as heparan sulfate. Sulfate groups at all positions were shown to be of importance for the binding. Fibroblasts bind PRELP, and this interaction is inhibited with heparin, suggesting a function for PRELP as a linker between the matrix and cell surface proteoglycans.

Amino Acid Sequence↗
PubMed1999

IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation.

Anti-TNF-alpha treatment of rheumatoid arthritis patients markedly suppresses inflammatory disease activity, but so far no tissue-protective effects have been reported. In contrast, blockade of IL-1 in rheumatoid arthritis patients, by an IL-1 receptor antagonist, was only moderately effective in suppressing inflammatory symptoms but appeared to reduce the rate of progression of joint destruction. We therefore used an established collagen II murine arthritis model (collagen-induced arthritis(CIA)) to study effects on joint structures of neutralization of either TNF-alpha or IL-1. Both soluble TNF binding protein and anti-IL-1 treatment ameliorated disease activity when applied shortly after onset of CIA. Serum analysis revealed that early anti-TNF-alpha treatment of CIA did not decrease the process in the cartilage, as indicated by the elevated COMP levels. In contrast, anti-IL-1 treatment of established CIA normalized COMP levels, apparently alleviating the process in the tissue. Histology of knee and ankle joints corroborated the finding and showed that cartilage and joint destruction was significantly decreased after anti-IL-1 treatment but was hardly affected by anti-TNF-alpha treatment. Radiographic analysis of knee and ankle joints revealed that bone erosions were prevented by anti-IL-1 treatment, whereas the anti-TNF-alpha-treated animals exhibited changes comparable to the controls. In line with these findings, metalloproteinase activity, visualized by VDIPEN production, was almost absent throughout the cartilage layers in anti-IL-1-treated animals, whereas massive VDIPEN appearance was found in control and sTNFbp-treated mice. These results indicate that blocking of IL-1 is a cartilage- and bone-protective therapy in destructive arthritis, whereas the TNF-alpha antagonist has little effect on tissue destruction.

Animals↗
PubMed1990

An immunohistochemical study of the distribution of matrical proteins in the mandibular condyle of neonatal mice. II. Non-collagenous proteins.

This study has illustrated the localisation of several non-collagenous proteins in the extracellular matrix of neonatal condylar cartilage (chondrocalcin, proteoglycans and a 100 kDa protein). Also, it has been shown that chondrocytes synthesise laminin and anchorin CII. The bone trabeculae in the primary spongiosa reacted positively for chondrocalcin, osteopontin and BMP. The cartilaginous wealth of collagens (Type I, II, VI, IX, X and XI), together with the various non-collagenous proteins, are considered to possess an important role in the maintenance of chondrogenic expression as well as in the regulation of cartilage differentiation by means of an interaction with the undifferentiated precursor cells.

Animals↗
PubMed1989

Human growth hormone enhances chondrogenesis and osteogenesis in a tissue culture system of chondroprogenitor cells.

GH is a systemic promoter of skeletal growth which increases the synthesis of insulin-like growth factor I in parenchymal tissues as well as in peripheral tissues such as the liver and growing cartilage. The present study was designed to examine whether GH possesses a direct effect on cellular proliferation and differentiation in mouse condylar cartilage. Cartilage progenitor cells were cultured in the form of a tissue culture on top of collagen sponges in medium containing 10% fetal calf serum and were treated with 50 ng/ml GH for 6 days. Three-day incubation with GH caused a marked increase in DNA synthesis and in the size of the culture, which developed into a nodule of differentiated chondrocytes and a well developed perichondrial layer around it. The effect of GH was even more pronounced after 6 days in culture; at which time a distinct network of trabeculae was noted throughout the extracellular matrix. The trabeculae contained osteocyte-like cells and were in close contact with both osteoblast-like and osteoclast-like cells. Using antibodies against bone-specific antigens, i.e. osteocalcin and osteopontin, provided further support for the notion that the newly formed trabecular formation was comprised of bone matrical components. Untreated control cultures lacked such structures, but contained hyaline-like cartilage. It, therefore, seems reasonable to suggest that GH induces a strong stimulatory effect on progenitor cell proliferation, cartilage differentiation, and extracellular mineralization, which supports de novo bone formation in vitro.

Alkaline Phosphatase↗
PubMed1988

Growth and repair of cartilage: organ culture system utilizing chondroprogenitor cells of condylar cartilage in newborn mice.

The zone of progenitor cells of mandibular condyles of neonatal mice was kept in an organ culture system for up to 8 days. Qualitative and quantitative determinations indicated a pronounced proliferative activity during the initial phases of the culture followed by a differentiation phase and the acquisition of typical hyaline cartilage. The mature hypertrophic chondrocytes were found to be surrounded by cartilage-specific macromolecules such as type II collagen, cartilage proteoglycans, and cartilage anchorin. The extracellular mineralization proceeded along matrix vesicles as is usually noted in vivo. A unique finding in this study was the observation that explants comprising cartilage progenitor cells and their adjacent extracellular matrix succeeded in repairing the damaged condylar in vitro.

Animals↗
PubMed1987

Evidence for sequential appearance of cartilage matrix proteins in developing mouse limbs and in cultures of mouse mesenchymal cells.

The initiation of synthesis and the accumulation of four cartilage matrix proteins (type II collagen and three noncollagenous proteins, one of Mr 148, one of Mr 59, and an oligometric protein of Mr above 500 with 100-kDa subunits, respectively) were studied in developing mouse limbs and in cultures of limb bud mesenchyme by means of immunolocalization. On day 13 of gestation, type II collagen was observed throughout the entire humerus, whereas the 148-kDa protein was localized only in the central portion. Neither the 100-kDa-subunit protein nor the 59-kDa protein could be demonstrated in the humerus at that stage. On day 14 1/2, type II collagen and the 148-kDa protein were codistributed throughout the humerus. The 100-kDa-subunit protein was detectable in the periphery of the humerus, whereas little 59-kDa protein could yet be demonstrated. On day 18, all four proteins being studied could be detected immunologically in the developing mouse humerus. They differed in immunolocalization. Type Ii collagen, the 148-kDa protein, and the 100-kDa-subunit protein were codistributed throughout the distal and proximal parts of the cartilage. However, the 148-kDa protein could no longer be detected immunochemically in the outermost part of the cartilage in the proximal shoulder joint. The 148-kDa protein codistributed with type II collagen and the 100-kDa-subunit protein in the distal cartilaginous region, where joint development was less advanced. On the other hand, the 59-kDa protein was not demonstrated directly within the hyaline cartilaginous structures, but surrounded the entire structure. This protein was also present in the same part of the proximal joint region as that in which the 148-kDa protein was not detected. To develop an in vitro model for studies of skeletogenesis, mesenchymal cells prepared from mouse limb buds were cultured as micromass cultures at high initial cell density to favor chondrogenesis. On day 3 of culture, type II collagen was the only protein that could be detected immunochemically in the cultures, whereas on day 6 the 148-kDa protein was demonstrated, and a few chondrocytes in the central portion of each cartilaginous nodule were associated with the 100-kDa-subunit protein. The 59-kDa protein could not yet be immunochemically detected.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1980

Oligosaccharides on proteoglycans from the swarm rat chondrosarcoma.

Two classes of oligosaccharides were identified in alkaline borohydride digests of monomer proteoglycans from the Swarm rat chondrosarcoma. The first class consists of three similar oligomers, each of which is linked to the proteoglycan core proteins by an O-glycosidic bond between N-acetylgalactosamine and hydroxyl groups on serine and threonine. The structures of the two smallest oligosaccharides are: (formula: see text). Proteoglycan monomers from the chondrosarcoma contain about 1.3 of these oligosaccharides for every chondroitin sulfate chain. Their structures and distribution on the core protein suggest that they are related to the linkage region between keratan sulfate chains and the core protein of cartilage proteoglycans. The second class of oligomers consists of oligosaccharide-peptides that contain mannose and are probably linked to the core protein by N-glycosylamine bonds to asparagine. There appear to be about 15 of these oligosaccharides/ proteoglycan molecule, and they are primarily located on the core protein nearer to the hyaluronic acid-binding site than both the oligosaccharides linked by O-glycoside bonds and the chondroitin sulfate chains. Chondrocytes isolated from the chondrosarcoma and grown in culture synthesize both classes of oligosaccharides.

Acetylgalactosamine↗