Lysyl Hydroxylase 3 Glucosylates Galactosylhydroxylysine Residues in Type I Collagen in Osteoblast Culture

Sricholpech, Marnisa; Perdivara, Irina; Nagaoka, Hideaki; Yokoyama, Megumi; Tomer, Kenneth B.; Yamauchi, Mitsuo

doi:10.1074/jbc.m110.178509

Cited by 59 publications

(118 citation statements)

References 78 publications

(100 reference statements)

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“…Hydroxylation of specific Lys residues catalyzed by LHs is an important modification because it determines the fate of the cross-linking pathway and provides the glycosylation sites in type I collagen (2,17,18). Mutations in the LH-encoding genes lead to various connective diseases, but it has also become clear that defects in specific ER chaperones/foldases result in aberrant LH functions, suggesting that these ER proteins also control the functionality of LHs.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for this specificity is not clear at present. Considering the fact that these are the major glycosylation sites of type I collagen (17,40), Lys hydroxylation at these sites may occur in the context of sequential modifications involving multiple enzymes, i.e. LH1, glycosyltransferases such as a glycosyltransferase 25 domain 1 (GLT25D1) and LH3, a complex process in which CypB may be required.…”

Section: Discussionmentioning

confidence: 99%

“…Lysine Hydroxylation and Hydroxylysine GlycosylationLevels of Lys hydroxylation and mono-(G-) and diglycosylation (GG-) of Hyl residues of collagen were quantified by HPLC as reported (17). In CypB KO mouse collagen, the extent of Lys hydroxylation was moderately but significantly decreased by 22-28% as compared with those from WT and Het mice (p Ͻ 0.001) (Table 1A).…”

Section: Histological Analysis Of Collagen Matrix In Tendon-mentioning

confidence: 99%

“…To determine the level of glycosylated Hyl, collagen samples were also subjected to base hydrolysis with 2 N NaOH. GG-Hyl, G-Hyl, and free Hyl in the hydrolysates were separated with a specific gradient program on HPLC and quantified as residues/collagen molecule as reported (17).…”

Section: Methodsmentioning

confidence: 99%

“…Another divalent cross-link, DHLNL, identified only in KO, was only found to be in the GG (32%) or free (68%) form. The residue ␣1-87 (␣2-87 in rodent type I collagen) is not glycosylated (17), and the major glycosylation site (Table 3) is also the major helical cross-linking site to form DHLNL (␣1-16 C ϫ ␣1-87) (40). The ratio of GG-DHLNL to free DHLNL indeed corresponds well to that of Hyl at ␣1-87 (Table 3) and is consistent with the increased Lys hydroxylation in the C-telopeptide (Fig.…”

Section: Histological Analysis Of Collagen Matrix In Tendon-mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Histological Analysis Of Collagen Matrix In Tendon-mentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Histological Analysis Of Collagen Matrix In Tendon-mentioning

confidence: 99%

See 3 more Smart Citations

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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Dental Implants and Osseous Healing in the Oral Cavity

Mizutani

Yamashita

2018

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Mechanical Loading Stimulates Expression of Collagen Cross‐Linking Associated Enzymes in Periodontal Ligament

Kaku

Rocabado

Kitami

et al. 2015

Journal Cellular Physiology

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Type I collagen, a major extracellular component of the periodontal ligament (PDL), is post-translationally modified by a series of specific enzymes. Among the collagen-modifying enzymes, lysyl oxidase (LOX) is essential to initiate collagen cross-linking and lysyl hydroxylases (LHs) to regulate the cross-linking pathways that are important for tissue specific mechanical properties. The purpose of this study was to investigate the effects of mechanical loading on the expression of collagen-modifying enzymes and subsequent tissue changes in PDL. Primary human PDL cells were subjected to mechanical loading in a 3D collagen gel, and gene expression and collagen component were analyzed. Wistar rats were subjected to excessive occlusal loading with or without intra-peritoneal injection of a LOX inhibitor, β-aminopropionitrile (BAPN). Upon mechanical loading, gene expression of LH2 and LOX was significantly elevated, while that of COL1A2 was not affected on hPDL-derived cells. The mechanical loading also elevated formation of collagen α-chain dimers in 3D culture. The numbers of LH2 and LOX positive cells in PDL were significantly increased in an excessive occlusal loading model. Notably, an increase of LH2-positive cells was observed only at the bone-side of PDL. Intensity of picrosirius red staining was increased by excessive occlusal loading, but significantly diminished by BAPN treatment. These results demonstrated that mechanical loading induced collagen maturation in PDL by up-regulating collagen-modifying enzymes and subsequent collagen cross-linking which are important for PDL tissue maintenance. J. Cell. Physiol. 231: 926-933, 2016. © 2015 Wiley Periodicals, Inc.

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Lysyl Hydroxylase 3 Glucosylates Galactosylhydroxylysine Residues in Type I Collagen in Osteoblast Culture

Cited by 59 publications

References 78 publications

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

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

Dental Implants and Osseous Healing in the Oral Cavity

Mechanical Loading Stimulates Expression of Collagen Cross‐Linking Associated Enzymes in Periodontal Ligament

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