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PubMed1983

Changes in the structure and chemical composition of the mandibular condylar cartilage of the neonatal mouse.

The cartilage of the mandibular condyle of growing mice was used to monitor changes in the content of protein, DNA, hydroxyproline, hydroxylysine, uronic acid, calcium and phosphate. Protein and DNA increased in a stepwise fashion with one spurt seen during the first 2 weeks of post-natal life a second immediately after weaning. Hydroxyproline increased during the entire growth period, i.e. until the 8th post-natal week. Hydroxylysine increased only until week 4. The content of the uronic acid fluctuated and showed highs and lows throughout the growth period. Both calcium and phosphate increased in an almost parallel fashion from birth until the stage of tissue maturation. Morphological studies indicated that the hyaline type of cartilage in the newborn is gradually replaced by a fibrous tissue, which reveals a markedly different structure and composition.

Animals↗
PubMed1989

Collagen metabolite excretion as a predictor of bone- and skin-related complications in spinal cord injury.

Immediately after the trauma, spinal cord injury patients have an increased rate of collagen synthesis and an even greater increase of collagen degradation. Collagen lost from bone is implicated in the etiology of osteoporosis and heterotopic ossification, and collagen lost from skin might lead to a propensity to develop pressure ulcers. The urinary excretion of two collagen metabolites has been monitored and their fluctuation related to the onset of skin or bone complications in these patients. One metabolite, glucosyl-galactosyl hydroxylysine, is more abundant in skin collagen; the other, galactosyl hydroxylysine, is more abundant in bone collagen. The excretion of both metabolites increases after injury, reaching a peak between three and six months after injury, and declines gradually, reaching control values about a year after injury. If a skin pressure ulcer develops, the urinary excretion of the diglycoside remains elevated instead of gradually decreasing. Similarly, if osteoporosis or heterotopic ossification is diagnosed, the monoglycoside excretion does not return to control values until the bone turnover stabilizes. Monitoring of the urinary excretion of both glycosides might prove helpful in prompting early examination to establish the presence of emerging skin and bone complications. Thus, aggressive preventive therapy could be given sooner.

Adolescent↗
PubMed1975

Hydroxylation of lysyl residues in lysine-rich and arginine-rich histones by lysyl hydroxylase in vitro.

Lysine-rich and arginine-rich histones were examined as substrates for lysyl hydroxylase. Both proteins are known to be rich in lysyl residues, and lysine-rich histone also contains -X-Lys-Gly-sequences, whereas no such sequences are found in the arginine-rich histone. Both histones were found to be hydroxylated by lysyl hydroxylase, and the time courses of the hydroxylation reactions with these substrates were linear for at least 60 min. The Km values observed where 3 - 10(-6)M for heat-denatured lysine-rich histone and 6 - 10(-6)M for heat-denatured arginine-rich histone. Heat-denatured lysine-rich histone was hydroxylated at a higher rate than non-denatured both at 37 and 25 degrees C. No such phenomenon was found, however, when arginine-rich histone was examined as a substrate. Furthermore, at 37 degrees C lysine-rich histone was a better substrate for lysyl hydroxylase then arginine-rich histone, but this relationship was reversed at 25 degrees C. The synthesis of hydroxylysine observed with arginine-rich histone indicates that the lysyl hydroxylase preparation used in these experiments catalyzes the synthesis of hydroxylysine not only in the sequence -X-Lys-Gly-, but also in some other sequences. Certain collagen polypeptide chains are known to contain one hydroxlysyl residue in a sequence other than -X-Lys-Gly-, and the present results may explain this finding.

Amino Acid Sequence↗
PubMed1975

Comparison of the cyanogen bromide peptides of insoluble guinea-pig skin and scar collagen.

Insoluble guinea-pig skin collagen and insoluble dermal scar collagen were cleaved with CNBr and the peptides derived from the alpha1-chain were separated by ion-exchange and molecular-sieve chromatography. Comparison of the peptides from scar collagen with those from skin collagen showed that the former contained more hydroxylysine. Separation of the CNBr peptides showed that this increase in hydroxylysine was found not only in the non-helical regions, but was also seen down the helical portion of the molecule. Separation of the peptides revealed the presence of more peptides in digests of skin collagen than those of scar, and these have been attributed to the presence of Type III collagen in skin, but no evidence was found for the presence of this Type III collagen in dermal scar tissue.

Amino Acids↗
PubMed1977

The collagen of heart valve.

A hydroxylysine-rich type I collagen has been isolated from pepsin-digested porcine heart valve. The ratio of alpha1 to alpha2 in the isolated molecule was 2:1. The component alpha chains exhibited unusual chromatographic behavior in comparison to corresponding chains from human dermis and lathyritic rat skin collagen. The composition of component cyanogen bromide peptides identified the alpha chains as authentic type I chains and demonstrated hydroxylysine enrichment throughout the length of the chain. delta6-Dehydro-5,5'dihydroxylysinonorleucine, a collagen cross-link derived from two hydroxylysyl residues and ordinarily found in hard tissue collagens was found to be the predominant cross-link in heart valve.

Amino Acids↗
PubMed1979

Biochemical abnormalities of the human diabetic glomerular basement membrane.

Since the biochemical composition of the diabetic glomerular basement membrane is still a controversial area, a study was carried out using kidneys from seven diabetic and seven nondiabetic subjects. In diabetic membranes, the glycine, hydroxylysine, glucose, galactose, and hydroxylysine-linked disaccharide unit content was increased together with a decrease in the half-cystine and sialic acid content. These findings support the view of a biochemical alteration in the human diabetic glomerular basement membrane.

Adult↗
PubMed1982

Composition, cross-linking and thermal stability of bone and skin collagens in patients with osteogenesis imperfecta.

The composition, cross-linking, and thermal stability of the collagens were determined in bone and skin biopsies from 4 patients with moderate to severe forms of osteogenesis imperfecta (OI). The major modification observed with respect to control subjects was an overhydroxylation of lysine in type I bone collagen (hydroxylysine content doubled in three patients and increased by 50% in the last patient). This overhydroxylation is confirmed by a similar increase in the dihydroxylated cross-link of bone collagen: the dehydrodihydroxylysinonorleucine. The type II collagen from cartilage and the pepsin-soluble collagens from the skin of these patients contained the normal amount of hydroxylysine. A small amount of type III collagen has been found in three patients, while only in one patient a slight increase in the type III/type I collagen ratio was observed in skin. In all patients the thermal stability of the collagen triple helix, measured by differential scanning calorimetry, was normal in both bone and skin. Although in at least three patients the clinical features allowed us to classify our patients into two different groups (Sillence et al., 1979 classification--groups I and III), the biochemical results are similar, suggesting that the overhydroxylation of the lysine in type I bone collagen is a common feature of severe forms of osteogenesis imperfecta.

Adolescent↗
PubMed1978

Isolation of a collagen fraction from the body-wall glycoproteins of the leech (Hirudo medicinalis), and characterization of its carbohydrate--amino acid portion.

Fractionation of the leech (Hirudo medicinalis) body-wall glycoproteins yielded a collagen fraction containing only D-glucose and D-galactose as its carbohydrate constituents. Digestion of the collagen with trypsin and pronase, and alkaline degradation of the resulting glycopeptides, gave a product that contained a disaccharide linked to hydroxylysine. Mild, acid hydrolysis of the N-acetylated glycopeptides yielded a disaccharide consisting of a D-glucose and a D-galactose residue. Various chemical and enzymic reactions of the disaccharide, the glycosyloxylysine, and the glycopeptide fraction indicated that the disaccharide is 2-O-alpha-D-glucopyranosyl-D-galactose, and that this is beta-glycosidically linked to O-5 of the hydroxylysine residue in the collagen.

Animals↗
PubMed1984

Some properties of the reactive hydroxylysyl residues in collagen: their possible role in nucleation during fibril formation.

Native or heat-denatured collagens were incubated under controlled conditions of temperature and pH with variable molar ratios of KCNO or 2,4,6-trinitrobenzene sulphonic acid. The results obtained suggest that a small number of free amino groups are available for reaction on the native protein, while all the free amino groups react on the denatured protein. The highly reactive free amino groups in the native protein are hydroxylysine residues and have an abnormally low pK of 8.5 which is conformation dependent; this pK becomes normalized upon denaturation of the protein. The reactive hydroxylysines appear to be located in basic regions that could be the nucleation sites needed for fiber formation in the heat-gelation assay; the modified protein does not form stable fibrils upon heating at 37 degrees C and the few fibers formed are not stabilized after reduction with NaBH4. Our results also suggest that the triple helix in collagen is heterogeneous with respect to the reactivity of free amino groups and that several discrete transition temperatures are observed with two main breaks at 30 degrees C and at 37 degrees C, respectively.

Animals↗
PubMed1989

Biosynthesis of collagen crosslinks. II. In vivo labelling and stability of lung collagen in rats.

Rat lung collagen was labelled in vivo by a single intraperitoneal injection of [3H]lysine at several key timepoints in lung development: days 11 (alveolar proliferation), 26 (start of equilibrated growth), 42 (end of equilibrated growth), and 100 (adult lung structure present). The rates of deposition of labelled hydroxylysine and the difunctional, Schiff base-derived crosslinks hydroxylysinonorleucine (HLNL) and dihydroxylysinonorleucine (DHLNL) were quantified. We also measured total lung content of the trifunctional, mature crosslink hydroxypyridinium (OHP) in these same animals. While the relative rates of accumulation of labelled collagen [3H]hydroxylysine differed by a factor of about 6 at the different times of injection of labelled precursor, quantitative and qualitative patterns of collagen crosslinking were very similar at all of the lung developmental stages studied. Furthermore, there was little or no breakdown of the lung collagen pool as defined by the presence of labelled crosslinks; changes in lung DHLNL content could be completely accounted for by its maturation to OHP, regardless of the age of the rats when injected with the radioactive precursor. We conclude that mature, crosslinked collagen in the lungs of rats, which is obligatorily an extracellular pool, is not being degraded at a measurable rate. Therefore, studies of others that have shown apparent high rates of breakdown of newly synthesized collagen in lungs of whole animals using different methods are probably not reflective of the metabolic fate of total lung collagen, and may indicate that degradation of normal lung collagen occurs predominantly or exclusively intracellularly.

Animals↗
PubMed1998

Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance.

Bone collagen cross-links are now widely used to assess bone resorption levels in many metabolic bone diseases. The post-translational modifications of bone and other mineralizing collagens are significantly different from those of other type I collagen matrices, a fact that has been exploited during recent advances in the development of biochemical markers of bone resorption. The enzymatic collagen cross-linking mechanism is based upon aldehyde formation from specific telopeptide lysine or hydroxylysine residues. The immature ketoimine cross-links in bone form via the condensation of a telopeptide aldehyde with a helical lysine or hydroxylysine. Subsequent maturation to the pyridinoline and pyrrole cross-links occur by further reaction of the ketoimines with telopeptide aldehydes. In mineralizing tissues, a relatively low level of lysyl hydroxylation results in low levels of hydroxylysyl pyridinoline, and the occurrence of the largely bone specific lysyl pyridinoline and pyrrolic cross-links. The collagen post-translational modifications appear to play an integral role in matrix mineralization. The matrix of the turkey tendon only mineralizes after a remodeling of the collagen and the subsequent formation of a modified matrix more typical of bone than tendon. Further, disturbances in the post-translational modification of collagen can also affect the mineralization density and crystal structure of the tissue. In addition to their use as a convenient measure of matrix degradation, collagen cross-links are of significant importance for the biomechanical integrity of bone. Recent studies of osteoporotic bone, for example, have demonstrated that subtle perturbations in the pattern of lysine hydroxylation result in changes in the cross-link profile. These alterations, specifically changes in the level of the pyrrolic cross-link, also correlate with the strength of the bone. Further research into the biochemistry of bone collagen cross-links may expand current understanding and their clinical application in metabolic bone disease. This review also demonstrates the potential for further study into this area to provide more subtle information into the mechanisms and etiology of disease and aging of mineralizing tissues.

Aging↗
PubMed1975

Stable, nonreducible cross-links of mature collagen.

During in vivo maturation, and also during in vitro incubation with physiological buffers, native collagen fibers display a progressive increase in tensile strength and insolubility. Paralleling these physiologically important changes is a progressive loss of the reducible cross-links which initially join the triple-chained subunits of collagen fibers. Although there is evidence suggesting that the reducible cross-links are gradually transformed into more stable, nonreducible cross-links during maturation, the nature of the transformation process and the structure of the stable "mature" cross-links has remained a mystery. In order to test the possibility that cross-link transformation involves addition of a nucleophilic amino acid residue to the reducible cross-links, histidine, arginine, glutamate, aspartate, lysine, and hydroxylysine residues were chemically modified, and the effect of each modification procedure on the in vitro transformation of reducible cross-links was ascertained. The results of these experiments indicated that destruction of histidine, arginine, glutamate, and aspartate residues has no measurable effect on the rate and extent of reducible cross-link transformation in hard tissue collagens. In contrast, modification of lysine and hydrocylysine residues with a wide variety of specific reagents completely blocks the transformation of reducible cross-links. Removal of the reversible blocking groups from lysine and hydroxlylysine residues then allows the transformation to proceed normally. These results indicate that collagen maturation involves nucleophilic addition of lysine and/or hydroxylysine residues to the electrophilic double bond of the reducible cross-links, yielding derivatives which are not only more stable but also capable of cross-linking more collagen molecules than their reducible precursors.

Amino Acids↗
PubMed1979

Excretion and synthesis of basement membrane disaccharide units in Masugi nephritis.

During nephrotoxic nephritis in the rat, an increased urinary excretion of glucosyl-galactosyl hydroxylysine and of galactosyl-hydroxylysine has been observed in the autologous phase of the disease. This due mainly to an elevation of the polypeptide-bound fraction of these hydroxylysyl glucosides with a molecular weight over 1,000 daltons. The levels of both urinary hydroxylysyl glucosides were correlated with proteinuria. Their increased excretion appears to originate in the lysed glomerular basement membrane. At the same stage of nephrotoxic nephritis, an increased glucosyl transferase activity could be demonstrated in the isolated glomeruli, correlated with albuminuria, attesting a higher turn-over of the disaccharide units of the glomerular basement membrane.

Albuminuria↗
PubMed1971

The isolation, and amino acid and carbohydrate composition, of polymeric collagens prepared from various human tissues.

1. Insoluble polymeric collagens from various human tissues were prepared by the EDTA method. Almost all of the collagen from simple soft tissues such as dermis, tendon, submucosa, sclera and cornea could be extracted, whereas the more complex tissues such as intercostal cartilage and intervertebral disc yielded only small amounts of collagen. Amino acid and carbohydrate analysis indicated that most of the preparations were highly purified on the basis of their tyrosine, hexosamine, mannose, xylose and fucose contents. 2. Wide variation in the total hexose content was observed, the lowest being 8.5 residues/3000 amino acid residues for collagen from dermis and the highest being 42.1 residues/3000 in corneal collagen. The molar ratios of sugars also varied, submucosal collagen having a galactose/glucose ratio of 1.0 and corneal collagen having a ratio of 2.3. 3. The presence of glucosylgalactosylhydroxylysine was confirmed in submucosal collagen by compositional and chromatographic analysis of this component after its isolation from alkaline hydrolysates of the collagen. Evidence was also obtained for the presence of galactosylhydroxylysine. 4. Determination of the hydroxylysyl glycosides was carried out and it was observed that the amounts of these components varied widely from tissue to tissue. Corneal collagen contained 19.1 hydroxylysine-linked carbohydrate units/3000 amino acid residues, whereas tendon collagen contained only 4.1 units/3000. Variation in the ratio disaccharide unit/monosaccharide unit was also observed, the ratio being 1.2 in intercostal cartilage collagen and 4.1 in submucosal collagen. The proportion of the total hydroxylysine that was substituted by carbohydrate also varied from tissue to tissue.

Amino Acids↗
PubMed1973

The chemistry of the collagen cross-links. Age-related changes in the reducible components of intact bovine collagen fibres.

The change in the amounts of the three major reducible cross-links was followed throughout the bovine-life span. The major reducible cross-link in embryonic skin is 6,7-dehydro-N(epsilon) -(2-hydroxy-5-amino-5-carboxypentyl)hydroxylysine, but this is gradually replaced in the latter stages of gestation or early postnatal growth period by two other Schiff bases, 6,7-dehydro-N(epsilon)-(5-amino-5-carboxypentyl)hydroxylysine and a component not yet identified, designated Fraction C. These latter two Schiff bases increase in amount during the rapid growth period to a maximum, after which they then slowly decrease until at maturity they are virtually absent. The proportion of these Schiff bases closely reflects the rate of growth, i.e. the amount of newly synthesized collagen present at any one time. Similarly, the three Schiff bases present in tendon and the one in cartilage slowly decrease during maturation. No evidence for the possible stabilization of these aldimine bonds during maturation by reduction in vivo was found by three different analytical techniques. Concurrently with the decrease in the proportion of the Schiff bases some new reducible components increased during maturation, but their characterization as N(epsilon)-glycosylamines demonstrated that they were not related to the lysine-derived aldehyde components. The significance of these components in the aging process cannot at present be assessed. As no evidence was obtained for any new reducible cross-links replacing the Schiff bases, it is probable that the latter are intermediate cross-links and that during maturation they are stabilized to some as yet unknown non-reducible cross-link as previously proposed (Bailey, 1968).

Achilles Tendon↗
PubMed1980

N6-Trimethyl-lysine metabolism. Structural identification of the metabolite 3-hydroxy-N6-trimethyl-lysine.

(1)H and (13)C nuclear-magnetic-resonance spectroscopy and functional-group analysis were used to determine the molecular structure of an isolated metabolite (II(b)) of trimethyl-lysine as 3-hydroxy-N(6)-trimethyl-lysine, an important intermediate in the conversion of trimethyl-lysine into trimethylammoniobutyrate and carnitine [Hoppel, Cox & Novak (1980) Biochem. J.188, 509-519]. Functional-group analysis revealed the presence of a primary amine and reaction of metabolite (II(b)) with periodate yielded 4-N-trimethylammoniobutyrate as a product, showing 2,3-substitution on the molecule and suggesting that the 3-substitution on the molecule may be an alcohol ([unk]CH-OH), amine ([unk]CH[unk]-NH(2)) or carbonyl ([unk]C=O) functional group. (1)H integration ratios, (1)H and (13)C chemical-shift data and (1)H and (13)C signal multiplicities from the sample (II(b)) were used to complete the identification of metabolite (II(b)) as 3-hydroxy-N(6)-trimethyl-lysine. For example, the proton multiplet at delta 4.2p.p.m. and doublet at delta 4.1p.p.m., positions representative of amine or alcohol substitution on methylene carbon atoms, integration ratios of 1:1:2:9:4 and a positive ninhydrin test suggest 3-hydroxy-N(6)-trimethyl-lysine as the molecular structure for metabolite (II(b)). (13)C chemical-shift data obtained from the sample (II(b)) and compared with several model compounds (trimethylammoniohexanoate, trimethyl-lysine and 3-hydroxylysine) resulted in generation of the spectrum of the metabolite and allowed independent identification of metabolite (II(b)) as 3-hydroxy-N(6)-trimethyl-lysine. The (1)H spectrum of erythro- and threo-3-hydroxylysine are presented for comparison, and the (1)H and (13)C n.m.r. spectra of the erythro-isomer support this analysis.

Carbon Radioisotopes↗
PubMed1981

Characterization of N-glycosylated type I collagen in streptozotocin-induced diabetes.

The N epsilon-glycosylation of lysine and hydroxylysine residues in collagen from streptozotocin-induced-diabetic rats was confirmed and the stability of the complex shown to be due to an Amadori rearrangement. The studies also demonstrate the relative specificities of glucose, galactose and mannose in their reaction with collagen. The glycosylation of lysine in vitro occurs with glucose and galactose, but not with mannose, whereas only gucose reacts with hydroxylysine to any significant extent. Glycosylation of collagen occurs slowly during normal aging, but in contrast with reports suggesting accelerated aging of collagen in diabetic animals, we clearly demonstrated that the apparent increased stability is not due to an acceleration of the normal maturation process involving the reducible cross-links.

Animals↗
PubMed2002

Putative role of lysyl hydroxylation and pyridinoline cross-linking during adolescence in the occurrence of osteoarthritis at old age.

OBJECTIVE: The collagen network in human articular cartilage experiences a large number of stress cycles during life as it shows hardly any turnover after adolescence. We hypothesized that, to withstand fatigue failure, the physical condition of the collagen network laid down at adolescence is of crucial importance for the age of onset of osteoarthritis (OA). METHODS: We have compared the lysyl hydroxylation level and pyridinoline cross-link level of the collagen network of degenerated (DG) cartilage of the femoral knee condyle (representing a preclinical early stage of OA) with that of normal cartilage from the contralateral knee. The biological age of the collagen network was determined by means of pentosidine levels. For each donor, collagen modifications of normal cartilage were compared with DG cartilage that showed no significant remodeling of the collagen network (as evidenced by identical pentosidine levels). RESULTS: DG cartilage contained significantly more hydroxylysine residues per collagen molecule in comparison with healthy cartilage from the same donor, both in the upper and lower half (the region near the articular surface and adjacent to bone, respectively). In addition, a significantly higher level of pyridinoline cross-linking was observed in the upper half of DG cartilage. Considering the biological age of the collagen network, the changes observed in DG cartilage must have been present several decades before cartilage became degenerated. CONCLUSIONS: The data suggest that high levels of lysyl hydroxylation and pyridinoline cross-linking result in a collagen network that fails mechanically in long term loading. Areas containing collagen with low hydroxylysine and pyridinoline levels are less prone to degeneration. As such, this study indicates that post-translational modifications of collagen molecules synthesized during adolescence are causally involved in the pathogenesis of OA.

Aged↗