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Beardsworth LJ, Eyre DR & Dickson IR (1990): Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. J. Bone Miner. Res. 5. 671.
Bienkowski RS, Cowan MJ, McDonald, JA & Crystal RG (1978): Degradation of newly synthesized collagen. J. Biol. Chem. 253, 4356-4363.
Black D, Duncan A & Robins SP (1988): Quantitative analysis of the pyridinium crosslinks of collagen in urine using ion-paired reversed-phase high-performance liquid chromatography. Anal. Biochem. 169, 197-203.
Branca F, Robins SP, Ferro-Luzzi A & Golden MHN (1992): Bone turnover in malnourished children. Lancet 340, 1493-1496.
Chen Q, Fitch JM, Linsenmayer C & Linsenmayer TF (1992): Type X collagen: Covalent crosslinking to hypertrophic cartilage-collagen fibrils. Bone Miner. 17, 223-1227.
Colle M, Ruffie A & Ruedas E (1988): Osteocalcin in children with short stature. Acta Paediatr. Scand 333, (Suppl.), 196-197.
Deftos LJ, Wolfert RL, Hill CS & Burton DW (1992): Two-site assays of bone ala protein (ostoecalcin) demonstrate immunochemical heterogeneity of the intact molecule. Clin. Chem. 38, 2318-2321.
Delmas PD (1992): Clinical use of biochemical markers of bone remodeling in osteoporosis. Bone 13, (Suppl. 1), S17-S21.
Delmas PD, Chatelain P, Malaval L & Bonne G (1986): Serum bone Gla-protein in growth hormone deficient children. J. Bone Miner. Res. 1, 333-338.
Delmas PD, Christiansen C, Mann KG & Price PA (1990): Bone Gla Protein (Osteocalcin); Assay standardization report. J. Bone Miner. Res. 5, 5-11.
Demers L (1992): New biochemical marker for bone disease: is it a breakthrough? Clin. Chem. 38, 2169-2170.
(Editorial) (1992): Pyridinium crosslinks as markers of bone resorption. Lancet 340, 278-279.
Eyre DR (Editorial, 1992): New markers of bone resorption. J. Clin. Endocrinol. Metab. 74, 470A - C.
Eyre DR, Koob TJ & VanNess KP (1984): Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal. Biochem. 137, 380-388.
Eyre DR, Dickson IR & VanNess KP (1988): Collagen crosslinking in human bone and cartilage: age-related changes in the content of mature hydroxypyridinium residues. Biochem. J. 252, 495-500.
Hanson DA, Weis ME, Bollen A, Maslan SL, Singer FS & Eyre DR (1992): A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen crosslinked N-telopeptides in urine. J. Bone Miner. Res., 7, 1251-1258.
Hassager C, Jensen LT, Johansen JS, Riis BJ, Melkko J, Podenphant J, Risteli L, Christiansen C & Risteli J (1991): The carboxy-terminal propeptide of type I procollagen in serum as a marker of bone formation: the effect of nandrolone decanoate and female sex hormones. Metabolism 40, 205-208.
Hassager C, Risteli J, Risteli L, Jensen SB & Christiansen C (1992): Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy pre-menopausal women. J. Bone Miner. Res. 7, 1307-1311.
Hauschka PV, Lian JB, Cole DEC & Gundberg CM (1989): Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol. Rev. 69, 990-1047.
Heinegard D & Oldberg A (1989): Structure and biology of cartilage and bone matrix noncollagenous macromolecules. FASEB J 3, 2042-2051.
Heinegard D & Saxne T (1991): Molecular markers of processes in cartilage in joint disease. Br. J. Rheumatol. 30, (Suppl. 1), 21-24.
Hinek A, Reiner A & Poole AR (1987): The calcification of cartilage matrix in chondrocyte culture: studies of the C-propeptide of type II collagen (chondrocalcin). J. Cell Biol. 104, 1435-1441.
Johansen JS, Jensen SB, Riis BJ, Rasmussen L, Zachmann M & Christiansen C (1990): Serum bone ala protein: a potential marker of growth hormone (GH) deficiency and the response to GH therapy. J. Clin. Endocrinol. Metab. 71, 122-126.
Kanzaki S, Hosoda K, Moriwake T, Tanaka H, Kubo T, Inoue M, Higuchi J, Yamaji T & Seino Y (1992): Serum propeptide and intact molecular osteocalcin in normal children and children with growth hormone (GH) deficiency: a potential marker of bone growth and response to GH therapy. J. Clin. Endocrinol. Metab. 75, 1104-1109.
Keene DR, Sakai LY & Burgeson RE (1991): Human bone contains type 111 collagen, type VI collagen, and fibrillin: type III collagen is present on specific fibers that may mediate attachment of tendons, ligaments, and periosteum to calcified bone cortex. J. Histochem. Cytochem. 39, 59-69.
Kielty CM, Kwan APL, Holmes DF, Schor SL & Grant ME (1985): Type X collagen, a product of hypertrophic chondrocytes. Biochem. J. 227, 545-554.
Knapen MHJ, Hamulyak K & Vermeer C (1989): The effect of vitamin K supplementation on circulating osteocalcin (bone ala protein) and urinary calcium excretion. Ann. Intern. Med. 111, 1001-1005.
Krane SM, Kantrowitz FG, Byrne M, Pinnell SR & Singer FR (1977): Urinary excretion of hydroxylysine and its glycosides as an index of collagen degradation. J. Clin. Invest. 59, 819-827
Melkko J, Niemi S, Risteli L & Risteli J (1990): Radioimmunoassay of the carboxyterminal propeptide of human type I procollagen. Clin. Chem. 36, 1328-1332.
Merle B & Delmas PD (1990): Normal carboxylation of circulating osteocalcin (bone ala protein) in Paget's disease of bone. Bone Miner. 11, 237-245.
Michaelsen KF, Johansen JS, Samuelson G, Price PA & Christiansen C (1992): Serum bone gamma-carboxy-glutamic acid protein in a longitudinal study of infants: lower values in formula-fed infants. Paediatr. Res. 31, 401-405.
Moro L, Modricky C, Rovis L & DeBernard B (1988): Determination of galactosyl hydroxylysine in urine as a means for the identification of osteoporotic women. Bone Miner. 3, 271-276.
Moro L, Gazzarrini C, Crivellari D, Galligioni E, Talamini R & Debernard B (1993): Biochemical markers for detecting bone metastases in patients with breast cancer. Clin. Chem. 39, 131-134.
Nissen R, Cardinale GJ & Udenfriend S (1978): Increased turnover of arterial collagen in hypertensive rats. Proc. Natl. Acad. Sci. USA 75, 451-453.
Niyibizi C, Wu J-J & Eyre DR (1987): The carboxypropeptide trimer of type II collagen is a prominent component of immature cartilages and intervertebral-disc tissue. Biochim. Biophys. Acta 916, 493-499.
Pinnell SR, Fox R & Krane SM (1971): Human collagens: differences in glycosylated hydroxylysines in skin and bone. Biochim. Biophys. Acta 229, 119-122.
Plantalech L, Guillaumont M, Vergnaud P, Leclercq M & Delmas PD (1991): Impairment of gamma carboxylation of circulating osteocalcin (Bone Gla Protein) in elderly women. J. Bone Miner. Res. 6, 1211-1216.
Pratt DA, Danilof Y, Duncan A & Robins SP (1992): Automated analysis of the pyridinium crosslinks of collagen in tissue and urine using solid-phase extraction and reversed-phase high-performance liquid chromatography. Anal. Biochem. 207, 168-175.
Price PA, Otsuka AS, Poser JW, Kristaponis J & Raman N (1976): Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc. Natl. Acad. Sci. USA 73, 1447-1451
Price PA, Williamson MK & Lothringer JW (1981): Origin of the vitamin K-dependent bone protein found in plasma and its clearance by kidney and bone. J. Biol. Chem. 256, 12760-12766.
Reiser KM & Last JA (1986): Biosynthesis of collagen crosslinks: in vivo labelling of neonatal skin, tendon, and bone in rats. Connect. Tissue Res. 14, 293-306.
Risteli L (1990): The carboxyterminal propeptide of procollagen type I (PICP) in serum and biological fluids. Scand. J. Clin. Lab. Invest. 202, (Suppl.), 143-146.
Risteli J, Elomaa I, Niemi S, Novamo A & Risteli L (1993): Radioimmunoassay for the pyridinoline crosslinked carboxy-terminal peptide of type I collagen: a new serum marker of bone collagen degradation. Clin. Chem. 39, 635-640.
Robins SP (1982): Turnover and crosslinking of collagen. In Collagen in health and disease, eds JB Weiss & MIV Jayson, pp. 160-178. Churchill Livingstone.
Robins SP (1983): Crosslinking of collagen: isolation, structural characterization and glycosylation of pyridinoline. Biochem. J. 215, 167-173.
Robins SP (1988): Functional properties of collagen and elastin. Baillieres Clin. Rheumatol. 2, 1-36.
Robins SP, Stewart P, Astbury C & Bird HA (1986): Measurement of the crosslinking compound, pyridinoline, in urine as an index of collagen degradation. Ann. Rheum. Dis. 45, 969-973.
Robins SP, Duncan A & Riggs BL (1990): Direct measurement of free hydroxy-pyridinium crosslinks of collagen in urine as new markers of bone resorption in osteoporosis. In Osteoporosis 1990, eds C Christiansen & K Overgaard, pp. 465-468. Copenhagen: Osteopress.
Robins SP, Black D, Paterson CR, Reid DM, Duncan A & Seibel MJ (1991): Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases. Eur. J. Clin. Invest. 21, 310-315.
Saggese G, Bertelloni S, Baroncelli GI & Di Nero G (1992): Serum levels of carboxyterminal propeptide of type I procollagen in healthy children from 1st year of life to adulthood and in metabolic bone diseases. Eur. J. Pediatr. 151, 764-768.
Saxne T & Heinegard D (1989): Involvement of non-articular cartilage, as demonstrated by release of cartilage-specific protein, in rheumatoid arthritis. Arthritis Rheum. 32, 1080-1086.
Saxne T & Heinegard D (1992): Cartilage oligomeric matrix protein: a novel marker of cartilage turnover detectable in synovial fluid and blood. Br. J. Rheumatol. 31, 583-591.
Segrest JP & Cunningham LW (1970): Variations in human urinary O-hydroxylysyl glycoside levels and their relationship to collagen metabolism. J. Clin. Invest. 49, 1497-1509.
Seibel MJ, Duncan A & Robins SP (1989): Urinary hydroxy-pyridinium crosslinks provide indices of cartilage and bone involvement in arthritic diseases. J. Rheumatol. 16, 964-970.
Seibel MJ, Gartenberg F, Silverberg SJ, Ratcliffe A, Robins, SP & Bilezikian JP (1992): Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 74, 481-486.
Seyedin S, Kung VT, Daniloff YN, Hesley RP, Gomez B, Nielsen LA, Rosén HN & Zuk RF (1993): Immunoassay for urinary pyridinoline: the new marker for bone resorption. J. Bone Min. Res. 8, 635-641.
Smedsrod B, Melkko J, Risteli L & Risteli J (1990): Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells. Biochem. J. 271, 345-50.
Tapanainen P, Risteli L, Knip M, Kaar M-L & Risteli J (1988): Serum aminoterminal propeptide of type m procollagen: a potential predictor of response to growth hormone therapy. J. Clin. Endocrinol. Metab. 67, 1244-1249.
Taubman MB, Kammerman S & Goldberg B (1976): Radioimmunoassay of procollagen in serum of patients with Paget's disease of bone. Proc. Exp. Biol. Med. 152, 284-287.
Thonar E J-M A, Lenz ME, Klintworth GK, Caterson B, Pachman LM, Glickman P, Katz R, Huff J & Kuettner KE (1985): Quantification of keratan sulphate in blood as a marker of cartilage metabolism. Arthritis Rheum. 28, 1367-1376.
Tracy RP, Andrianorivo A, Riggs BL & Mann KG (1990): Comparison of monoclonal and polyclonal antibody-based immunoassays for osteocalcin: a study of sources of variation in assay results. J. Bone Miner. Res. 5, 451-461.
Trivedi P, Cheeseman P, Portman B, Hegarty J & Mowat AP (1985): Variation in serum type III procollagen peptide with age in healthy subjects and its comparative value in the assessment of disease activity in children and adults with chronic active hepatitis. Eur. J. Clin. Invest. 15, 69-74.
Van der Rest M & Garrone R
(1991): Collagen family of proteins. FASEB J 5, 2814-2829.
One would like to express the results of crosslink marker assays as a function of an individual's bone mass. Since bone mass cannot be directly measured, inferences are made from body height, and circulating crosslink markers are expressed in relation to body height raised to a certain power. There is some discussion on what is the most appropriate power factor to use. Unfortunately the scientific literature does not contain a lot of information on the skeletal mass of children. It is very likely that, as for a height-independent measure of body weight, the optimal factor changes with age. If one had a very large series of normal values for skeletal mass at different ages, one could transform it into SD scores and make a regression model, but the baseline data for that are not available yet. Preliminary data from a longitudinal study using bone mass data obtained by dual energy X-ray absorptiometry (DEXA) suggests that an exponent of 3 can be used for normal children (Branca). In a study of malnourished children, whose skeletal mass per unit height was lower than in normal children, Golden found an exponent of 2 most appropriate.
Crosslinks are the end product of different processes (diurnal cycles in hormone production, etc., and perhaps small growth spurts). The day-to-day variation of crosslink secretion is about 15%, which one would like to interpret as actual variation in growth, but at present it is not yet possible to distinguish within this variation the experimental error from a biological response. Better growth measures, as will perhaps be obtained by knemometry, may contribute to the solution of this problem.
A question was put about the marker for the turnover of collagen in soft tissues. The main collagen pool is skin, which accounts for about 25% of body weight and which contains both type I and type III collagen. In the experiment of Dickerson and Widdowson, skin collagen was more labile than that of either muscle or bone (Cabak, Dickerson & Widdowson, 1963). Part of the reason for that is that there are differences in cross-linking pathways, but this has nothing to do with differences in turnover rate. In experiments in which a radio-label was incorporated into the skin of malnourished animals and the animals were then refed to produce catch-up growth, the total amount of label stayed the same. Therefore, although there was a large amount of growth of the skin, what seemed to happen was that the lattice-work expanded and filled in with more collagen, rather than the collagen being resorbed and replaced.
Part of the discussion dealt with the usefulness of osteocalcin as an indicator, for instance of growth velocity. In his paper, Robins had mentioned its use as an early outcome measure of growth hormone therapy. The main problems seem to be a persisting uncertainty as to whether or not serum levels reflect production levels, and the lack of systematic information on the osteocalcin content of different bones at different ages. It does not seem to be stoichometrically related to mineralization. In Senegal, Ndiaye et al. (in press) found reduced osteocalcin levels in malnourished children suffering from kwashiorkor which increased during recovery and became normal in half of them, but no differences in osteocalcin levels between stunted and non-stunted marasmic children.
Several discussants would like to
know what the different markers are indicative of and under what circumstances one should
use one or the other. It does not seem possible yet to answer such questions, and in most
situations it is recommended to use several markers in an attempt to further clarify their
Cabak V, Dickerson, JWT & Widdowson EM (1963): Response of young rats to deprivation of protein and of calories. Br. J. Nutr. 17, 601-616.
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