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PubMed2001

Urinary collagen metabolite excretion in amyotrophic lateral sclerosis.

Collagen abnormalities of the spinal cord and the skin have been reported in patients with amyotrophic lateral sclerosis (ALS). The urinary concentrations of the hydroxylysine glycosides, i.e., glucosylgalactosyl hydroxylysine (glu-gal Hyl) and galactosyl hydroxylysine (gal Hyl), indicate the tissue origin of the collagen metabolites and the rate of the degradation of collagen. We measured the urinary levels of glu-gal Hyl and gal Hyl in 12 ALS patients, 10 diseased control subjects with other neurologic or muscular diseases (Control Group A), and 10 healthy control subjects (Control Group B). The urinary level of glu-gal Hyl in ALS patients was significantly lower than in the two control groups. In addition, a significant negative relationship between glu-gal Hyl urinary level and duration of illness was found in ALS patients. There was no marked difference in the urinary level of gal Hyl between ALS patients and the control groups. Our data suggest that the decreased urinary level of glu-gal Hyl may be useful in assessing the alteration in collagen metabolism in ALS and may have a relationship with the progression of ALS.

Aged↗
PubMed1977

Biochemical basis of skeletal defects induced by hydralazine: inhibiton of collagen synthesis and secretion in embryonic chicken cartilage in vitro.

Hydralazine (1-hydrazinophthalazine) produces skeletal defects resembling those observed in experimentally induced manganese deficiencies. Since glycosylation of collagen, a step preceding its secretion, requires Mn2+, the effect of hydralazine on collagen secretion and the formation hydroxylysine glycosides was examined in explants of embryonic chicken long-bone rudiments. Auto-radiographic studies showed that hydralazine blocked collagen secretion. Secretion was restored by Fe2+ alone or Fe2+ + Mn2+ but not by Mn2+ alone, suggesting that a Fe2+-requiring step was involved. Biochemical analyses showed that hydralazine inhibited the formation of hydroxylysine, a step requiring Fe2+, but it did not inhibit the formation of hydroxylysine-glocosides by Mn2+-requiring steps, although the reaction was inhibited in vitro. Hydralazine also failed to inhibit intracellular mucopolysaccharide synthesis which involves several Mn2+-requiring enzymes. These observations suggest that the deleterious effects of hydralazine on bones are caused by its inhibition of hydroxylation steps in collagen synthesis.

Abnormalities, Drug-Induced↗
PubMed1976

The origin of urinary hydroxylysyl glycosides in Paget's disease of bone and in primary hyperparathyroidism.

The urinary excretion of glucosyl-galactosyl-hydroxylysine and of galactosyl-hydroxylysine were studied in Paget's disease of bone and in primary hyperparathyroidism. Both metabolites were increased in these diseases. Although glucosyl-galactosyl-hydroxylysine is not abundant in bone collagen, it is possible that a part of it originates from calcified tissue.

Alkaline Phosphatase↗
PubMed1978

Chemical characterization of glomerular and tubular basement membranes of cattle of different ages.

Glomerular and tubular basement membranes were isolated from fetal, neonatal, young and adult bovine kidneys. An isolation method with sieves for both glomeruli and tubules from the same kidney was developed. A detergent procedure appeared to give purer glomerular and tubular basement membrane preparations than the generally used sonication method. No large differences were found in the composition of glomerular and tubular basement membrane of adult animals. Glomerular and tubular basement membrane preparations of the four age groups showed an increase with age of hydroxylysine and both 3- and 4-hydroxyproline. The most marked increases appeared at different stages of development, that of tubular basement membrane being between fetal and neonatal stages and glomerular basement membrane between 18 weeks old and adult animals. The ratio of 3- to 4-hydroxyproline increased considerably during development. Total imino acid content was higher for both types of basement membrane from adult than from young animals, while total content of hydroxylysine plus lysine remained fairly constant. The increase in hydroxylation of lysine was accompanied by a corresponding change in glucose and galactose content so that the ratio of galactose to hydroxylysine or glucose to galactose remained constant. Fucose content of both types of basement membranes was the same for all age groups but content of aminosugars and mannose gradually increased with age.

Aging↗
PubMed1996

Lung collagen cross-links in rats with experimentally induced pulmonary fibrosis.

Rats were intratracheally instilled with bleomycin or with silica (quartz) dust to induce lung fibrosis. Several weeks later, purified collagen chains (or collagen digests) were isolated from the lungs of these animals and from age-matched controls instilled intratracheally with saline solution, and the ratios of hydroxylysine to lysine and of the dysfunctional cross-links DHLNL to HLNL were quantified. Collagen from fibrotic lungs had significantly higher ratios of DHLNL:HLNL than did control lungs, 15.5 +/- 4.8 and 17.1 +/- 4.8 vs. 2.3 +/- 0.5 for the silica-instilled and the bleomycin-instilled animals, respectively. The hydroxylysine:lysine ratio was significantly increased for the alpha 1(I) chain, to a value 170% of that of lung collagen from control animals, and for several of its constituent CNBr peptides. Lung tissue was exhaustively digested with collagenase and specific cross-linked peptides were isolated and characterized. The cross-linked alpha 1(I) x alpha 1(I) peptide linked by the residues 87 x 16C, with a ratio of DHLNL:HLNL of 17:1, demonstrated that the increased hydroxylation of the dysfunctional cross-links in fibrotic lung collagen could be accounted for in part by increased hydroxylation of the lysine residue at position 16C of the C-terminal telopeptide of the collagen alpha 1(I) chain. It proved impossible to locate the corresponding N-terminal cross-linked fragment from alpha 1(I) x alpha 1(I) chains, 9N x 930, possibly due to further reactions of this material to form the material referred to as poly(CB6). Isolated poly (CB6) accounted for more than half of the total alpha 1(I)CB6 peptide expected in lung collagen, and had a hydroxylysine:lysine content 2.8 times greater in bleomycin-treated animals than in their age-matched controls. Evidence was also found for a cross-linked alpha 1(III) x alpha 1(I) peptide linking residue 87 from the alpha 1(III) chain with residue 16C from the alpha 1(I) chain; it also had an increased ratio of DHLNL:HLNL. We conclude that the increased hydroxylation of lysine observed in two different animal models of lung fibrosis occurs preferentially at the N- and C-terminal nonhelical extension peptides of the alpha 1(I) collagen chains, and that this apparent specificity of overhydroxylation of fibrotic collagen may have important structural and pathological consequences.

Amino Acid Sequence↗
PubMed1978

Inherited human collagen lysyl hydroxylase deficiency: ascorbic acid response.

A patient is described with congenital hypotonia, lax joints, friable skin, hemorrhagic scars, high-arched palate, and borderline microcornea. Acid hydrolyzed whole skin collagen had a reduced hydroxylysine content of 0.5 residues per 1,000 as compared to 5.1 +/- 0.7 in control skin. Collagen lysyl hydroxylase in dialyzed subcellular fractions of cultured skin fibroblasts required L-ascorbate as a principal cofactor. Activity of this enzyme in cultured skin fibroblasts derived from this patient, his father, and mother were 17%, 66%, and 39% of control values, respectively. Collagen prolyl hydroxylase activity was normal. Pharmacologic amounts of oral vitamin C (4 gm/day) produced an increase and withdrawal resulted in abrupt diminution of urinary excretion of hydroxylysine. Over a two-year period the patient's wound healing and muscle strength improved and corneal diameter increased. Hydroxylysine content of the skin did not increase.

Ascorbic Acid↗
PubMed2001

The fibril structure of type V collagen triple-helical domain.

Although the triple-helical structure of fibrillar collagen is regarded in general as being quite similar, each type of collagen molecule has inherent characteristics in the triple-helical domain. Few studies have ever been performed in terms of the aggregate structure of the triple-helical domain of fibrillar collagen. Reconstituted aggregates from the purified triple-helical domain of each type of fibrillar collagen might amplify the subtle differences in the structural characteristics of each type of collagen molecule. In this study, the reconstituted aggregate structure of pepsin-treated type V collagen (type Vp collagen), that is, virtually its triple-helical domain was characterized by transmission electron microscopy. Pepsin-treated type I (type Ip) and type II (type IIp) collagen were compared with type Vp collagen. Unique features of the aggregate structure of the triple-helical domain of the type V collagen can be summarized as follows:These results suggested that the lateral packing of the triple-helical domain of type V collagen is determined by its molecular structure. The characteristics of type Vp collagen fibrils might be explained by their characteristic amino acid composition. A significant feature of the triple-helical domain of type V collagen is the high content of glycosylated hydroxylysine residues. Molecular model building of the collagenous structure suggests that a change in surface roughness is conspicuous by incorporating the glycosylated hydroxylysine residues. More than a ten-fold content of bulky glycosylated hydroxylysine residues in type V collagen compared to that of type I might have a significant influence on both the intermolecular and interfibrillar interactions of the triple-helical domain of type V collagen molecule.

Amino Acid Sequence↗
PubMed1981

Nonenzymatic hydroxylations of proline and lysine by reduced oxygen derivatives.

The biosynthesis of trans-3- and trans-4-hydroxyprolines and 5-hydroxylysine in animal cells requires polypeptide proline or lysine, enzymes and cofactors including iron, and possibly involves peroxidatic intermediates. Several laboratories have reported the presence of low-molecular-weight hydroxyproline and hydroxylysine peptides in cell and organ cultures. We found that these small peptides contained the trans-3 and cis-4 isomers of hydroxyproline as well as trans-4 ones and that their production was not completely inhibited by alpha, alpha-dipyridyl, and iron chelator and effective inhibitor of enzyme-mediated hydroxylations. It is known that oxygen or hydrogen peroxide in the presence of metal can hydroxylate proline and other aromatic compounds. We show here that reduced oxygen derivatives can hydroxylate both free and polypeptide-bound proline and lysine, and that scavengers of hydroxyl radicals suppress, but do not completely inhibit, this reaction. Reduced oxygen derivatives can be generated in normal and pathological circumstances, and some of the low-molecular-weight hydroxyproline and hydroxylysine peptides found in cell and organ cultures might be derived from these derivatives and therefore do not reflect collagen turnover, but rather some other cellular activity.

Free Radicals↗
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↗
PubMed1978

Fibrodysplasia ossificans progressiva. Biochemical changes in blood serum, urine, skin, bone, and ectopic ossification.

Increased urinary output of total hydroxyproline, hydroxylysine and uronic acid was found in two patients suffering from fibrodysplasia ossificans progressiva. Before treatment of one of the patients, the high molecular weight peptide fraction deriving from newly synthesised collagen was particularly increased. Treatment with disodium etidronate (diphosphonate) reduced the values. The urinary values of sodium, potassium and calcium were also depressed during treatment, and, in both patients, serum phosphate was high, while serum calcium was normal. The hydroxyproline and hydroxylysine contents in skin and bone of FOP patients did not differ from controls, while ectopic ossifications showed a considerable increase in hydroxylysine in relation to normal bone.

Adolescent↗
PubMed1986

Collagen components in the duodenal and rectal mucosa in progressive systemic sclerosis and other diseases.

Small intestinal mucosa from 14 patients suffering from progressive systemic sclerosis and 22 patients with various other diseases was analysed for collagen components. There was no significant difference in the concentration of hydroxyproline, hydroxylysine and proline between the two groups. Rectal mucosa from 11 progressive systemic sclerosis patients, 5 patients with ulcerative colitis and 7 patients with various other diseases was analysed for collagen components. No significant difference was demonstrated in the concentration of hydroxyproline, hydroxylysine and proline between progressive systemic sclerosis patients and patients with various other diseases, but in patients with ulcerative colitis the concentration of hydroxyproline, hydroxylysine and proline were found to be significantly lower than in the two other groups.

Adolescent↗
PubMed1982

Collagen polymorphism in extracellular matrix of human osteosarcoma.

The collagenous matrix of human osteosarcoma was characterized biochemically and ultrastructurally. The highly cellular regions of the tumors contained many osteoblast-like cells filled with dilated rough endoplasmic reticulum. The extracellular matrix displayed a random weave of banded collagen fibrils (30--90 nm in diameter) interspersed with thinner, unbanded fibrils (15 nm in diameter). Tumors from 9 patients were analyzed for collagen composition. All gave a similar collagen profile. Three main molecular species of collagen were abundant: type I, type III, and type V, which occurred in the approximate proportions of 65:25:10. A high ratio of alpha 1(I) to alpha 2(I) chains suggested that one-third of the type I collagen was present as a type I trimer molecule. In contrast, normal bone matrix consisted almost exclusively of type I collagen. The fibrillar collagens in the soft tumor seemed unusually rich in hydroxylysine and hydroxylysine glycosides; type I collagen had two to three times the hydroxylysine content of normal bone collagen.

Adolescent↗
PubMed1980

Biochemical characterization of collagens synthesized by intestinal epithelial cell cultures.

Rat intestinal epithelial cells in culture synthesize and secrete several different collagens as identified by biochemical and ultrastructural criteria. These collagens were labeled with [U-14C]proline, separated by DEAE- and CM-cellulose chromatography, and at least four different collagen chains were identified. Two of them, present almost exclusively as fully processed collagens, were alpha 1(I) and alpha 2 chains. The presence of a large excess of alpha 1 (I) chains over the normal ratio for type I collagen indicated that both type I collagen [alpha 1(I)]2 alpha 2 and [alpha 1(I)]3 or type I trimer were present both in the culture medium and in the extracellular matrix. The labeled alpha 1(I) chain had a CNBr peptide pattern superimposable on that of a standard alpha 1(I) chain from rat skin, but the intact radiolabeled chain differed from the standard in its migration on sodium dodecyl sulfate gels and elution position on CM-cellulose column and had a much higher hydroxylysine content. The other two collagen chains were present in the culture medium exclusively as partially processed procollagens. They constituted 60 to 70% of the collagenous proteins and had features corresponding to none of the known collagen types. They were separated by CM-cellulose chromatography and further characterized. Both contained interchain disulfide bonds in the pepsin-resistant portion of the molecule and, after pepsin digestion, eluted from CM-cellulose at lower salt concentrations than standard alpha 1(I) chain. One of them was characterized by a low hydroxyproline content and a high hydroxylysine content, with all the hydroxylysine present as glycosylgalactosyl derivative. The CNBr peptide patterns of these two unknown chains differed from each other, and did not correspond to those of any standard collagen chain examined. They may represent new collagen types specifically present in the intestinal basement membrane.

Animals↗
PubMed1980

Changes in tissue morphology and collagen composition during the repair of cortical bone in the adult chicken.

UNLABELLED: An animal model was developed to study the histology and collagen chemistry of healing cortical bone. A hole was cut through the cortex of the mid-shaft of the humerus of the adult chicken, which allowed for repair at a mechanically stable site. After one to two weeks the collagen of the repair tissue, which consisted principally of woven bone, contained almost three times as much hydroxylysine as the collagen of normal adult bone and thus resembled the collagen of embryonic long bones. By eight weeks, when lamellar one predominated, the hydroxylysine content had fallen to normal levels. Type I was the major genetic type of collagen present throughout. No type-II collagen, characteristic of cartilage, was detected; this was consistent with the histological findings. The results established that hydroxylysine-rich type-I collagen can be made by osteoblasts of adult animals as well as by those of embryos and early postnates. CLINICAL RELEVANCE: In order to understand the biological characteristics of fracture healing, it is vital to study not only the macroscopic organization of the repair tissue but also the chemical properties of its molecular components. The strength of healing fractured bone, and indeed of normal bone, depends largely on the properties of the structural protein collagen. To date, it is not known whether the collagen in healing fractures is the same as that in normal bone, or whether it has distinct chemical features that may suit it for bone repair.

Animals↗
PubMed1985

Anglerfish pancreatic islets produce two forms of somatostatin-28.

It has been predicted on the basis of cDNA sequence analysis that anglerfish pancreatic islets contain at least two different preprosomatostatins (I and II). The C-terminal amino acid sequences of preprosomatostatin I and II were predicted to be identical to mammalian hypothalamic somatostatin-14 (SS-14) and its analog [Tyr7, Gly10]SS-14, respectively. That SS-14 is expressed in anglerfish pancreatic islets, has been shown earlier in pulse-chase experiments and by chemical characterization. However, it was observed that [Tyr7, Gly10]SS-14 was not expressed as such, but as part of larger polypeptides. Pulse-chase experiments combined with reverse-phase high pressure liquid chromatography, amino acid analysis with two different chromatographic systems, and complete Edman degradation indicated that preprosomatostatin II is processed in anglerfish islets to two different forms of somatostatin-28 (SS-28). The primary structure of the major form containing hydroxylysine (Hyl) was determined to be: H-Ser-Val-Asp-Ser-Thr-Asn-Asn-Leu-Pro-Pro-Arg- Glu-Arg-Lys-Ala-Gly-Cys-Lys-Asn-Phe-Tyr-Trp-Hyl-Gly-Phe-Thr-Ser-Cys-OH. The amino acid sequence of the minor form differs only at residue 23 by substitution of lysine for hydroxylysine. This is the first time that hydroxylysine, an amino acid which characteristically occurs in collagen or collagen-like structures has been identified in a potential regulatory peptide. It can be speculated that this amino acid is formed by post-translational hydroxylation of a lysine C-terminally linked to a glycine residue and thus modified at a site which has been recognized as hydroxylation site in collagen or collagen-like structures. The biological consequences of this unusual modification are being investigated.

Amino Acid Sequence↗
PubMed1985

Thermal stability of collagen in relation to non-enzymatic glycosylation and browning in vitro.

Thermal stability measured by isometric contraction-relaxation force was examined in rat tail tendons after incubation in vitro in glucose or hydroxymethylfurfurale solutions at pH 7.4 using buffer systems of either phosphate or tris (hydroxymethyl)aminomethan. In the phosphate system, incubation with glucose (170 mmol/l) for 12 days was found to increase the thermal stability of the tendons by a factor 3. At the same time, glucose was found to be attached to the lysine and hydroxylysine residues of collagen, and reactive carbonyl compounds were formed in the solution. In the tris(hydroxymethyl)aminomethan system containing reactive amino groups (pK 8.1), glucose was also attached to the lysine and hydroxylysine residues, but only very small amounts of reactive carbonyl compounds were formed in the solutions and no changes in thermal stability were recorded. Incubation with hydroxymethylfurfurale itself was found to increase the thermal stability rapidly and markedly in the phosphate buffer systems. This effect was inhibited when the tris(hydroxymethyl)aminomethan buffer system was used. Buffer solutions with tris(hydroxymethyl)aminomethan, containing large amounts of free amino groups compared to the free amino groups of collagen, might interfere with the formation of cross-links formed by carbonyl groups derived from metabolic glucose and amino groups of collagen. The non-enzymatic glycosylation of lysine and hydroxylysine itself does not influence the thermal stability. Additional reactions appeared to be transformation into reactive carbonyl compounds, such as hydroxymethylfurfurale, with subsequent formation of thermally stable cross-links between the collagen molecules.

Animals↗
PubMed1996

Improved rapid method for the isolation, purification and identification of collagen glycosides.

An updated method for obtaining purified glucosylgalactosyl hydroxylysine (Glc-Gal-Hyl) is presented. Marine sponge is subjected to alkaline hydrolysis followed by ion-exchange chromatography and gel filtration. Identification is confirmed by consecutive mild acid hydrolysis of the extract to produce galactosyl hydroxylysine (Gal-Hyl) and hydroxylysine (Hyl). High-performance liquid chromatography (HPCL) with a sodium acetate-acetonitrile buffer and dabsyl chloride as the derivatizing agent demonstrated the purity of the extract and its hydrolyzates. Glc-Gal-Hyl is not commercially available but this easy and efficient method can provide large amounts of it for collagen metabolism studies.

Animals↗
PubMed1987

Ascorbate regulation of collagen biosynthesis in Ehlers-Danlos syndrome, type VI.

We studied two unrelated individuals with Ehlers-Danlos syndrome type VI, which is characterized by congenital hypotonia, lax joints, severe kyphoscoliosis, friable skin, and hemorrhagic hypotrophic scars. The diagnosis was confirmed by decreased hydroxylysine residues in dermal collagen and decreased collagen lysyl hydroxylase activities in their cultured skin fibroblasts. Despite the diminished hydroxylysine residues in dermal collagen from the probands, we found no differences in hydroxylysyl residues of collagen synthesized by fibroblasts in culture. When patient 1 was given oral sodium ascorbate (5 g/d) for 3 weeks, ascorbate concentrations increased two-fold in plasma and 300-fold in urine. Urinary excretion of hydroxylysine and hydroxyproline increased during ascorbate administration. After a 1-year interval, bleeding time, wound healing, and muscle strength improved. Ascorbate supplementation (50 micrograms/mL) to confluent fibroblasts cultured from the two patients and controls increased hydroxyprolyl and hydroxylysyl residues of fibroblasts four to seven and three to four-fold respectively. Total protein associated with the cell layer increased 14% to 32% without concomitant change in cellular DNA. Total soluble collagenous material recovered from culture media increased 61% to 103% with ascorbate supplementation. These studies demonstrate that ascorbate improves the clinical status of patients with impaired collagen lysyl hydroxylase activity by enhancing lysyl and prolyl hydroxylation and total collagen production.

Amino Acids↗