Lysyl Hydroxylase-2b Directs Collagen Cross-Linking Pathways in MC3T3-E1 Cells

Pornprasertsuk, S; Duarte, Wagner R.; Mochida, Yoshiyuki; Yamauchi, Mitsuo

doi:10.1359/jbmr.040323

Cited by 86 publications

(86 citation statements)

References 30 publications

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“…Coordinating these processes in the ECM are factors such as TGF-β, which increases the secretion of peptides that evoke inflammation, drive fibrosis, and promote metastasis; conversely, forces generated by the ECM can modulate TGF-β-induced intracellular signaling (58, 59). TGF-β of collagen cross-link that qualitatively affects fibrillogenesis and matrix organization (7,8). Furthermore, we showed that, even in the absence of other cellular and soluble factors, LH2 modified the migratory and invasive behavior of lung adenocarcinoma cells, suggesting that the physical parameters of the tumor microenvironment regulated by LH2 may modify the biological properties of tumor cells.…”

Section: Discussionmentioning

confidence: 83%

“…Mediating these changes are lysyl hydroxylases (LH1, LH2, and LH3) encoded by distinct procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) genes; these intracellular enzymes induce hydroxylation of Lys residues on collagen prior to the formation of triple helical pro-collagen molecules (6)(7)(8)(9)(10)(11). Following secretion of pro-collagen molecules into the extracellular space, the telopeptidyl Hyl residues undergo LOX-induced oxidative deamination into Hyl ald , which then forms Hyl ald -derived aldimine cross-links Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, LOX-induced oxidative deamination of telopeptidyl Lys residues forms a labile aldimine or an aldol condensation product that matures into unstable Lys ald -derived collagen crosslinks (LCCs) (12). We have shown that overexpression of LH2 in osteoblasts induces a switch in the predominant type of collagen cross-link from LCC to HLCC, which qualitatively affects fibrillogenesis and matrix organization (7,8). HLCCs are abundant in skeletal tissues that require high mechanical strength, whereas LCCs are abundant in soft connective tissues (4).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

Chen¹,

Terajima²,

Yang³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

Chen¹,

Terajima²,

Yang³

et al. 2015

J. Clin. Invest.

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143

188

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“…Similarly, it is not known what caused a preferential increase in deoxypyridinoline compared with pyridinoline in the early stages of fibrosis. This could be due to the differential expression of specific lysyl hydroxylase isoforms (28,37). More comprehensive analyses for collagen crosslinking/aldehydes and lysine hydroxylation are warranted to confirm the alteration in cross-linking pattern and to elucidate its molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury

Perepelyuk

Terajima²,

Wang

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Perepelyuk M, Terajima M, Wang AY, Georges PC, Janmey PA, Yamauchi M, Wells RG. Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol 304: G605-G614, 2013. First published January 17, 2013 doi:10.1152/ajpgi.00222.2012.-Liver fibrosis is characterized by excessive deposition of extracellular matrix proteins by myofibroblasts derived from hepatic stellate cells and portal fibroblasts. Activation of these precursors to myofibroblasts requires matrix stiffness, which results in part from increased collagen crosslinking mediated by lysyl oxidase (LOX) family proteins. The aims of this study were to characterize the mechanical changes of early fibrosis, to identify the cells responsible for LOX production in early injury, and to determine which cells in normal liver produce collagens and elastins, which serve as substrates for LOXs early after injury. Hepatocytes and liver nonparenchymal cells were isolated from normal and early-injured liver and examined immediately for expression of LOXs and matrix proteins. We found that stellate cells and portal fibroblasts were the major cellular sources of fibrillar collagens and LOXs in normal liver and early after injury (1 day after bile duct ligation and 2 and 7 days after CCl 4 injury). Activity assays using stellate cells and portal fibroblasts in culture demonstrated significant increases in LOX family enzymatic activity as cells became myofibroblastic. LOX family-mediated deoxypyridinoline and pyridinoline cross-links increased after CCl 4-mediated injury. There was a significant association between liver stiffness (as quantified by the shear storage modulus G=) and deoxypyridinoline levels; increased deoxypyridinoline levels were also coincident with significantly increased elastic resistance to large strain deformations, consistent with increased cross-linking of the extracellular matrix. These data suggest a model in which the liver is primed to respond quickly to injury, activating potential mechanical feed-forward mechanisms.collagen cross-linking; liver fibrosis; pyridinoline; deoxypyridinoline; extracellular matrix PATHOLOGICAL FIBROSIS is characterized by excessive accumulation of extracellular matrix (ECM) proteins, most notably fibrillar collagens. The majority of ECM in organ fibrosis is deposited by myofibroblasts, proliferative and motile cells characterized by expression of ␣-smooth muscle actin (␣-SMA), which migrate to the site of injury or differentiate from preexisting cells in the organ. In the liver, the major myofibroblast precursor cells are hepatic stellate cells and portal fibroblasts.Myofibroblast differentiation from precursor cells requires mechanical tension. This has been shown in vitro for general fibroblast-to-myofibroblast activation (14), as well as for hepatic stellate cell and portal fibroblast activation to myofibroblasts in the liver (19,36) and suggests that increases in liver stiffness precede myofi...

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“…4E) cross-links were not impacted. However, the DHLNL-to-HLNL ratio (DHLNL/HLNL), which reflects the lysyl hydroxylation status in collagen crosslinks (54) and is an index of the fibrotic status of tissue (63), was also increased (by 18%; Fig. 4F).…”

Section: ·Daymentioning

confidence: 99%

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Mižíková

Ruiz‐Camp

Steenbock

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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RE. Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia. Am J Physiol Lung Cell Mol Physiol 308: L1145-L1158, 2015. First published April 3, 2015 doi:10.1152/ajplung.00039.2015.-Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O 2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor ␤-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, ␤-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. lung development; elastin; collagen; lysyl oxidase; alveolarization POSTNATAL LUNG DEVELOPMENT in mice is characterized by a period of intensive growth and remodeling of the lung parenchyma, which rapidly (over a period of days) generates a large number of small alveoli and thus maximizes the alveolar surface area over which gas exchange can take place. Secondary septation, the generation of new septa from preexisting septa, which then divide the air spaces, peaks in mice between 4 and 7 days after birth and is largely complete 21 days after birth. In humans, secondary septation is already well underway during late stages of pregnancy, and thus occurs in utero, and continues several years into postnatal life. Disturbances to the formation of secondary septa, such as the arrested secondary septation associated with bronchopulmonary dysplasia (BPD) in humans, leads to malformed lung...

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Lysyl Hydroxylase-2b Directs Collagen Cross-Linking Pathways in MC3T3-E1 Cells

Cited by 86 publications

References 30 publications

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

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