The lysyl hydroxylase isoforms are widely expressed during mouse embryogenesis, but obtain tissue- and cell-specific patterns in the adult

Salo, Antti M.; Sipilä, Laura; Sormunen, Raija; Ruotsalainen, Heli; Vainio, Seppo; Myllylä, Raili

doi:10.1016/j.matbio.2006.08.260

Cited by 34 publications

(37 citation statements)

References 42 publications

(60 reference statements)

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“…Further studies showed that the glucosyltransferase activity site is required for LH3 to be secreted into the extracellular space (18,19). These findings are the basis of the current paradigm that LH3 is the only LH isoform with an extracellular function.…”

mentioning

confidence: 81%

Lysyl Hydroxylase 2 Is Secreted by Tumor Cells and Can Modify Collagen in the Extracellular Space

Chen

Guo

Terajima

et al. 2016

Journal of Biological Chemistry

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Edited by Amanda FosangLysyl hydroxylase 2 (LH2) catalyzes the hydroxylation of lysine residues in the telopeptides of fibrillar collagens, which leads to the formation of stable collagen cross-links. Recently we reported that LH2 enhances the metastatic propensity of lung cancer by increasing the amount of stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), which generate a stiffer tumor stroma (Chen, Y., et al. (2015) J. Clin. Invest. 125, 125, 1147-1162). It is generally accepted that LH2 modifies procollagen ␣ chains on the endoplasmic reticulum before the formation of triple helical procollagen molecules. Herein, we report that LH2 is also secreted and modifies collagen in the extracellular space. Analyses of lung cancer cell lines demonstrated that LH2 is present in the cell lysates and the conditioned media in a dimeric, active form in both compartments. LH2 colocalized with collagen fibrils in the extracellular space in human lung cancer specimens and in orthotopic lung tumors generated by injection of a LH2-expressing human lung cancer cell line into nude mice. LH2 depletion in MC3T3 osteoblastic cells impaired the formation of HLCCs, resulting in an increase in the unmodified lysine aldehyde-derived collagen cross-link (LCC), and the addition of recombinant LH2 to the media of LH2-deficient MC3T3 cells was sufficient to rescue HLCC formation in the extracellular matrix. The finding that LH2 modifies collagen in the extracellular space challenges the current view that LH2 functions solely on the endoplasmic reticulum and could also have important implications for cancer biology.Collagens are the main component of the extracellular matrix and the most abundant protein in mammals (1). Of the 29 types of collagen identified, fibrillar type I collagen is the most abundant and important in providing tissues and organs with form and mechanical strength. Type I collagen biosynthesis involves a series of post-translational modifications of nascent procollagen ␣ chains on the endoplasmic reticulum; for example, specific lysine (Lys) and proline (Pro) residues undergo hydroxylation, and hydroxylysine (Hyl) residues undergo mono-and di-glycosylation. In the extracellular space, telopeptidyl Lys and Hyl residues on collagen molecules are oxidatively deaminated by lysyl oxidases (LOXs), 4 producing the reactive aldehydes Lys ald and Hyl ald , respectively, which initiates a series of condensation reactions to form various covalent intermolecular cross-links involving juxtaposed Lys, Hyl, and histidine (His) residues on the neighboring molecules, resulting in the formation of Hyl ald -derived collagen cross-links (HLCCs) (2).HLCCs are generated through a series of intermediate steps involving multiple enzymatic reactions. For example, HLCCs are produced through the divalent iminium cross-links dehydro-hydroxylysinonorleucine (deH-HLNL) when paired with a juxtaposed Lys residue (i.e. Hyl ald XLys) on a neighboring molecule, and deH-dihydroxylysinonorlecine (deH-DHLNL) with a Hyl residue (i.e. Hyl ald X...

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confidence: 81%

Lysyl Hydroxylase 2 Is Secreted by Tumor Cells and Can Modify Collagen in the Extracellular Space

Chen

Guo

Terajima

et al. 2016

Journal of Biological Chemistry

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“…Our data thus demonstrate that the other two LH isoenzymes hydroxylate lysine residues effectively in the triple helical region, the large differences in the extent of the hydroxylysine deficiency probably being due to differences in the levels of the three isoenzymes in various tissues. The mRNAs of all three LH isoenzymes have been shown to be expressed in all human and mouse tissues analyzed (3)(4)(5)(6)11), but data on tissue-specific expression levels of the isoenzyme proteins are still very limited (29), and do not allow any comparisons to be made.…”

Section: Decreased Levels Of Hydroxylysine and Hp Cross-links In Plod1mentioning

confidence: 99%

Tissue-specific Changes in the Hydroxylysine Content and Cross-links of Collagens and Alterations in Fibril Morphology in Lysyl Hydroxylase 1 Knock-out Mice

Takaluoma

Hyry

Lantto

et al. 2007

Journal of Biological Chemistry

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We have generated mice with targeted inactivation of the Plod1 gene for lysyl hydroxylase 1 (LH1). Its human mutations cause Ehlers-Danlos syndrome VIA (EDS VIA) characterized by muscular hypotonia, joint laxity, and kyphoscoliosis. The Plod1 ؊/؊ mice are flaccid and have gait abnormalities. About 15% of them died because of aortic rupture and smooth muscle cells in non-ruptured Plod1 ؊/؊ aortas showed degenerative changes. Collagen fibrils in the Plod1 ؊/؊ aorta and skin had an abnormal morphology. The LH activity level in the Plod1 ؊/؊ skin and aorta samples was 35-45% of that in the wild type. The hydroxylysine content was decreased in all the Plod1 ؊/؊ tissues, ranging from 22% of that in the wild type in the skin to 75 and 86% in the femur and lung. The hydroxylysylpyridinoline crosslinks likewise showed decreases in all the Plod1 ؊/؊ tissues, ranging from 28 and 33% of that in the wild type in the aorta and cornea to 47 and 59% in femur and tendon, while lysylpyridinolines were increased. The hydroxylysines found in the Plod1 ؊/؊ collagens and their cross-links were evidently synthesized by the other two LH isoenzymes. Few data are available on abnormalities in EDS VIA tissues other than the skin. Plod1 ؊/؊ mice offer an in vivo model for systematic analysis of the tissue-specific consequences of the lack of LH1 activity and may also provide a tool for analyzing the roles of connective tissue in muscle function and the complex interactions occurring in the proper assembly of the extracellular matrix.Lysyl hydroxylase (LH, 2 EC 1.14.11.4) catalyzes the hydroxylation of lysine residues mainly but not exclusively in -X-LysGly-triplets in collagens and proteins with collagen-like sequences (1). The enzyme resides within the endoplasmic reticulum and has three human and mouse isoenzymes, LHs 1-3 (1-7). The hydroxylysine residues formed have two important functions: they are essential for the stability of the intermolecular cross-links that provide the collagen fibrils with their tensile strength and mechanical stability, and they serve as attachment sites for carbohydrate units, either the monosaccharide galactose or the disaccharide glucosylgalactose (1). Collagen cross-link formation occurs in the extracellular matrix and is initiated by the conversion of specific lysine or hydroxylysine residues in the telopeptides, i.e. the short non-triple helical ends of collagen molecules, into the aldehydes allysine or hydroxyallysine, respectively, catalyzed by lysyl oxidase (8). The telopeptides are connected with the triple helical part of an adjacent molecule by difunctional immature cross-links in the characteristic staggered array of collagen molecules in a fibril. The three main fibril-forming collagens, types I, II, and III, have four cross-linking sites, one in each telopeptide and two in the triple helical region, close to its N-and C-terminal ends (9). If the residue in the telopeptide is hydroxyallysine, the difunctional cross-links can mature into trifunctional non-reducible cross-links comprising lysylpyri...

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“…Three isoforms of LH are known, LH1-3, with LH2 being a telopeptide-specific lysyl hydroxylase that controls the relative proportions of pyridinoline and pyrrole cross-links. [10,31–33] Pyrrole cross-links may be interfibrillar and directly provide greater mechanical advantage than pyridinolines. [29,34] It is also possible that the ratio of pyrrole to pyridinoline cross-links controls mineralization and mechanical properties of bone, as suggested by decreases in mineralization observed with increased LH2 expression and pyridinoline levels.…”

Section: Introductionmentioning

confidence: 99%

Exercise increases pyridinoline cross-linking and counters the mechanical effects of concurrent lathyrogenic treatment

McNerny

Gardinier

Kohn

2015

Bone

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The collagen cross-link profile of bone, associated with bone strength and fracture toughness, is tightly regulated (affecting cross-link quantity, type, lysine hydroxylation and maturity) and may contribute to the improvements in bone quality during exercise. We hypothesized that 1) exercise promotes mature cross-link formation, 2) increased mature cross-linking is accompanied by shifts in lysine hydroxylation, and 3) these changes in collagen cross-link profile have positive effects on mechanical properties. Growing male C57Bl6 mice were treated with 30 min/day of running exercise, 350 mg/kg/day β-aminopropionitrile (BAPN) injected subcutaneously to inhibit enzymatic collagen cross-linking, or both exercise and BAPN, from 5 to 8 weeks of age. Bone collagen cross-linking profile, mechanical properties, morphology, and mineralization were measured from the tibiae. Cross-link measures, including immature, pyridinoline, pyrrole and pentosidine cross-links, ratios reflecting cross-link maturity and hydroxylation, and mineralization were tested for their importance to mechanical properties across 8 week groups through correlation analyses and step-wise linear regressions. BAPN treatment significantly reduced lysylpyridinoline, pyrrole, hydroxylysinorleucine, and total mature collagen cross-linking, resulting in decreased bone elastic modulus and increased yield strain despite a marginal increase in TMD. Exercise caused a shift toward pyridinoline cross-linking, with increased hydroxylysylpyridinoline and decreased pyrrole cross-linking resulting in total mature cross-linking and estimated tissue level mechanical properties matching sedentary control levels. Exercise superimposed on BAPN treatment increased total mature cross-linking from BAPN to control levels, but did so by increasing pyridinoline, not pyrrole, cross-links. Exercise also counteracted the BAPN effects on modulus and strain, without a change in TMD. Pyrrole cross-linking was the strongest correlate of modulus (r=0.470, p<0.01) and yield strain (r=−0.467, p<0.01). Cross-links with similar levels of telopeptide lysine hydroxylation to pyrrole (lysylpyridinoline and hydroxylysinorleucine) also correlated with modulus and strain to a lesser extent. In conclusion, exercise in growing mice promotes pyridinoline collagen cross-linking in bone, the resulting increase in total mature cross-linking is sufficient to counteract the mechanical effects of concurrent cross-link inhibition, and this responsiveness to loading is a potential means by which exercise might improve bone quality in diseased or otherwise compromised bone.

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The lysyl hydroxylase isoforms are widely expressed during mouse embryogenesis, but obtain tissue- and cell-specific patterns in the adult

Cited by 34 publications

References 42 publications

Lysyl Hydroxylase 2 Is Secreted by Tumor Cells and Can Modify Collagen in the Extracellular Space

Lysyl Hydroxylase 2 Is Secreted by Tumor Cells and Can Modify Collagen in the Extracellular Space

Tissue-specific Changes in the Hydroxylysine Content and Cross-links of Collagens and Alterations in Fibril Morphology in Lysyl Hydroxylase 1 Knock-out Mice

Exercise increases pyridinoline cross-linking and counters the mechanical effects of concurrent lathyrogenic treatment

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