Cross-Linking and Stereospecific Structure of Collagen in Mineralized and Nonmineralized Skeletal Tissues

Yamauchi, Mitsuo; Katz, Elton P.; Otsubo, Kazunori; Teraoka, Kayo; Mechanic, Gerald L.

doi:10.3109/03008208909050006

Cited by 76 publications

(57 citation statements)

References 9 publications

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“…Others have proposed that mineralization prevents further cross-linking. 28,29 These findings are consistent with our results, where the mineralization followed the development of the collagen network and continued to develop even after the collagen content reached its mature levels. Our study clearly indicates that the compositional and mechanical properties of bone change most during the early dynamic and rapid period of growth, that is, the first 3-6 months of life in the rabbit.…”

Section: Discussionsupporting

confidence: 82%

Collagen and mineral deposition in rabbit cortical bone during maturation and growth: Effects on tissue properties

Isaksson

Harjula

Koistinen

et al. 2010

Journal Orthopaedic Research

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ABSTRACT:We characterized the composition and mechanical properties of cortical bone during maturation and growth and in adult life in the rabbit. We hypothesized that the collagen network develops earlier than the mineralized matrix. Growth was monitored, and the rabbits were euthanized at birth (newborn), and at 1, 3, 6, 9, and 18 months of age. The collagen network was assessed biochemically (collagen content, enzymatic and non-enzymatic cross-links) in specimens from the mid-diaphysis of the tibia and femur and biomechanically (tensile testing) from decalcified whole tibia specimens. The mineralized matrix was analyzed using pQCT and 3-point bend tests from intact femur specimens. The collagen content and the Young's modulus of the collagen matrix increased significantly until the rabbits were 3 months old, and thereafter remained stable. The amount of HP and LP collagen cross-links increased continuously from newborn to 18 months of age, whereas PEN cross-links increased after 6 months of age. Bone mineral density and the Young's modulus of the mineralized bone increased until the rabbits were at least 6 months old. We concluded that substantial changes take place during the normal process of development in both the biochemical and biomechanical properties of rabbit cortical bone. In cortical bone, the collagen network reaches its mature composition and mechanical strength prior to the mineralized matrix. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J. Orthop. Res. 28: 1626Res. 28: -1633Res. 28: , 2010 Keywords: maturation; growth; aging; rabbit; bone; mechanical properties; composition Collagen is the principal structural component of bone matrix, accounting for about 1/3 of mineralized bone tissues. 1 During development, bone formation and growth rates are regulated by genetic and hormonal factors, and by external factors such as mechanical loading that interact to determine the final anatomy and strength of the skeleton. 1-3 During this period, bone also changes in its composition, structure, and function. The organic matrix changes its composition and structural organization, and mechanical stiffness increases with increased bone mineral density (BMD). 3,4 The majority (>80%) of the mineral can be found within the collagen fibril network, 5 but limited information is available about the factors that determine the normal deposition of mineral, for example, the timing and how this can determine the properties of the adult tissue.The structure and function of maturing and growing bone were studied in several animal models. 4,6,7 Most studies focused on bone development and growth in rabbits, investigating the development of the primary and secondary ossification centers or evaluating bone growth at the growth plate. [8][9][10] Other studies showed that BMD increases and biomechanical properties change concurrently during maturation and growth. 4,6 However, the development of the collagen framework has been less extensively studied. During development, at least in the equine, ...

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Section: Discussionsupporting

confidence: 82%

Collagen and mineral deposition in rabbit cortical bone during maturation and growth: Effects on tissue properties

Isaksson

Harjula

Koistinen

et al. 2010

Journal Orthopaedic Research

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“…The specific activity of the NaB 3 H 4 was determined by the method described previously (34,35). The reduced samples were washed with cold distilled water several times by repeated centrifugation at 4,000 ϫ g and lyophilized.…”

Section: Methodsmentioning

confidence: 99%

Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen

Terajima

Taga

Chen

et al. 2016

Journal of Biological Chemistry

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Covalent intermolecular cross-linking provides collagen fibrils with stability. The cross-linking chemistry is tissue-specific and determined primarily by the state of lysine hydroxylation at specific sites. A recent study on cyclophilin B (CypB) null mice, a model of recessive osteogenesis imperfecta, demonstrated that lysine hydroxylation at the helical cross-linking site of bone type I collagen was diminished in these animals (Cabral, W. A., Perdivara, I., Weis, M., Terajima, M., Blissett, A. R., Chang, W., Perosky, J. E., Makareeva, E. N., Mertz, E. L., Leikin, S., Tomer, K. B., Kozloff, K. M., Eyre, D. R., Yamauchi, M., and Marini, J. C. (2014) PLoS Genet. 10, e1004465). However, the extent of decrease appears to be tissue-and molecular site-specific, the mechanism of which is unknown. Here we report that although CypB deficiency resulted in lower lysine hydroxylation in the helical cross-linking sites, it was increased in the telopeptide cross-linking sites in tendon type I collagen. This resulted in a decrease in the lysine aldehyde-derived cross-links but generation of hydroxylysine aldehyde-derived cross-links. The latter were absent from the wild type and heterozygous mice. Glycosylation of hydroxylysine residues was moderately increased in the CypB null tendon. We found that CypB interacted with all lysyl hydroxylase isoforms (isoforms 1-3) and a putative lysyl hydroxylase-2 chaperone, 65-kDa FK506-binding protein. Tendon collagen in CypB null mice showed severe size and organizational abnormalities. The data indicate that CypB modulates collagen cross-linking by differentially affecting lysine hydroxylation in a site-specific manner, possibly via its interaction with lysyl hydroxylases and associated molecules. This study underscores the critical importance of collagen post-translational modifications in connective tissue formation.Collagens comprise a large family of structurally related extracellular matrix proteins (1). Among all of the genetic types of collagen identified, fibrillar type I collagen is the most abundant, providing tissues and organs with form and stability. It is a heterotrimeric molecule composed of two ␣1 chains and one ␣2 chain forming a long uninterrupted triple helix with short non-helical domains (telopeptide) at both N and C termini. One of the functionally important characteristics of collagen is its unique, sequential post-translational modifications of Lys residues. The modifications include hydroxylation and monoand diglycosylation of hydroxylysine (Hyl), 3 and oxidative deamination of Lys and Hyl in the N-and C-telopeptides followed by extensive covalent intermolecular cross-linking (2). It is now clear that defective Lys modifications of collagen cause and/or are associated with a broad range of connective tissue disorders, including Ehlers-Danlos syndrome type VIA (3), bronchopulmonary dysplasia (4), Kuskokwim syndrome (5), Bruck syndrome (6, 7), fibrosis (8), disuse osteoporosis (9), and cancer progression (10, 11). Our recent finding showed that a switch of collage...

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“…In fact, reducible crosslinks are always present in the skeleton of any age because remodeling is continual throughout life [43] and not all crosslinks mature due to mineralization and stereospecificity of enzymatic crosslinking [19]. A lower concentration of mature crosslinks is expected in secondary osteons compared with interstitial bone tissues, which is not affected by the bone remodeling process [43].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, enzymatic crosslinks in long-lived collagen do not accumulate with age presumably due to the limited hydroxylation of the lysine residue and the activity of lysyl hydroxylase. In fact, the formation of enzymatic crosslinks is rather stereospecific, and repeats of head-to-tail covalent bonds are necessary for proper mineralization [19].…”

Section: Introductionmentioning

confidence: 99%

Age-related effect on the concentration of collagen crosslinks in human osteonal and interstitial bone tissue

Nyman

Roy

Acuna

et al. 2006

Bone

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Collagen crosslinks are important to the quality of bone and may be contributors to the age-related increase in bone fracture. This study was performed to investigate whether age and gender effects on collagen crosslinks are similar in osteonal and interstitial bone tissues. Forty human cadaveric femurs were collected and divided into two age groups: Middle aged (42-63 years of age) and Elderly (69-90 years of age) with ten males and ten females in each group (n = 10). Micro-cores of bone tissue from both secondary osteons (newly formed) and interstitial regions (biologically old) in the medial quadrant of the diaphysis were extracted using a custom-modified, computer numerical controlled machine. The bone specimens were then analyzed using high performance liquid chromatography to determine the effects of age and gender on the concentration of mature, enzymatic crosslinks (hydroxylysyl-pyridinoline -HP and lysylpyridinoline -LP) and a non-enzymatic crosslink (pentosidine -PE) at these two bony sites. The results indicate that age has a significant effect on the concentration of LP and PE, while gender has a significant effect on HP and LP. In addition, the concentration of the crosslinks in the secondary osteons is significantly different from that in the interstitial bone regions. These results suggest that the rate of non-enzymatic crosslinking may increase while the formation of maturate enzymatic crosslinks may decrease with age. Such changes could potentially reduce the inherent quality of the bone tissue in the elderly skeleton.

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Cross-Linking and Stereospecific Structure of Collagen in Mineralized and Nonmineralized Skeletal Tissues

Cited by 76 publications

References 9 publications

Collagen and mineral deposition in rabbit cortical bone during maturation and growth: Effects on tissue properties

Collagen and mineral deposition in rabbit cortical bone during maturation and growth: Effects on tissue properties

Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen

Age-related effect on the concentration of collagen crosslinks in human osteonal and interstitial bone tissue

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