Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered cross-link pattern: Important pathogenetic steps in early and late stage of systemic scleroderma?

Brinckmann, Jürgen; Kim, S.; Wu, Jianqing; Reinhardt, Dieter P.; Batmunkh, C.; Metzen, Eric; Notbohm, Holger; Bank, Ruud A.; Krieg, Thomas; Hunzelmann, Nicolas

doi:10.1016/j.matbio.2005.07.002

Cited by 61 publications

(57 citation statements)

References 45 publications

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“…Spontaneous disc regression is currently believed to be a consequence of macrophage activity. [35,36] type XI [37] all over, mostly NP regulates fibril diameter (smaller if this collagen is more abundant) influencing mechanical properties [35,38] beaded-filament forming collagens type VI all over, mostly NP helps cell fixation to the matrix and facilitates collagen bundles' sliding and lubrication [39,40] FACIT collagens type IX NP maintains matrix integrity [41,42] type XII AF might regulate fibrillogenesis [29,43] [66,[74][75][76]. However, when an imbalance occurs, degradation products might trigger inflammation.…”

Section: The Origin Of Inflammation In Intervertebral Discmentioning

confidence: 99%

Inflammation in intervertebral disc degeneration and regeneration

Molinos

Almeida

Caldeira

et al. 2015

J. R. Soc. Interface.

335

256

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Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overview of IVD regenerative therapies that target key inflammatory players.

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Section: The Origin Of Inflammation In Intervertebral Discmentioning

confidence: 99%

Inflammation in intervertebral disc degeneration and regeneration

Molinos

Almeida

Caldeira

et al. 2015

J. R. Soc. Interface.

335

256

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“…Considering that only dimers seem to exhibit LH activity, our data provide a molecular explanation as to how mutations in FKBP10 result in an overall dramatic decrease in lysyl hydroxylation levels of collagen telopeptides, leading to diseases such as Bruck syndrome, type XI osteogenesis imperfecta, and Kuskokwim syndrome. It should be noted that a high level of pyridinoline crosslinks has been reported to be causally involved in fibrosis and tumor metastasis (28,(50)(51)(52)(53)(54). The increased stiffening of the matrix from accumulating cross-linked collagen is directly linked to the progression of both types of pathologies.…”

Section: Discussionmentioning

confidence: 99%

Disentangling mechanisms involved in collagen pyridinoline cross-linking: The immunophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2

Gjaltema

Stoel

Boersema

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Collagens are subjected to extensive posttranslational modifications, such as lysine hydroxylation. Bruck syndrome (BS) is a connective tissue disorder characterized at the molecular level by a loss of telopeptide lysine hydroxylation, resulting in reduced collagen pyridinoline cross-linking. BS results from mutations in the genes coding for lysyl hydroxylase (LH) 2 or peptidyl-prolyl cis-trans isomerase (PPIase) FKBP65. Given that the immunophilin FKBP65 does not exhibit LH activity, it is likely that LH2 activity is somehow dependent on FKPB65. In this report, we provide insights regarding the interplay between LH2 and FKBP65. We found that FKBP65 forms complexes with LH2 splice variants LH2A and LH2B but not with LH1 and LH3. Ablating the catalytic activity of FKBP65 or LH2 did not affect complex formation. Both depletion of FKBP65 and inhibition of FKBP65 PPIase activity reduced the dimeric (active) form of LH2 but did not affect the binding of monomeric (inactive) LH2 to procollagen Iα1. Furthermore, we show that LH2A and LH2B cannot form heterodimers with each other but are able to form heterodimers with LH1 and LH3. Collectively, our results indicate that FKBP65 is linked to pyridinoline cross-linking by specifically mediating the dimerization of LH2. Moreover, FKBP65 does not interact with LH1 and LH3, explaining why in BS triple-helical hydroxylysines are not affected. Our results provide a mechanistic link between FKBP65 and the loss of pyridinolines and may hold the key to future treatments for diseases related to collagen cross-linking anomalies, such as fibrosis and cancer.collagen cross-linking | lysyl hydroxylase | FKBP65 | Bruck syndrome | fibrosis C ollagen I is an essential component of the extracellular matrix (ECM) of tissues such as bone and skin, and is involved in a wide variety of biological processes. A deregulated synthesis of collagen type I results in pathologies ranging from severe bone and skin anomalies to fibrosis (1-5). Hydroxylation of specific lysine (Lys) residues into 5-hydroxylysine (Hyl) is performed by lysyl hydroxylases (LHs), also known as the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family. Collagens deposited in the ECM are stabilized by the formation of intermolecular crosslinks by members of the lysyl oxidase family, LOX and LOXL (6). Two collagen cross-linking pathways have been identified, the allysine route and the hydroxyallysine route (7). In the allysine route, a telopeptide Lys is oxidized by lysyl oxidases into an aldehyde; in the hydroxyallysine route, this occurs with a telopeptide Hyl. In turn, the reactive aldehydes interact with the Lys or Hyl residues in the helical part of collagen to form difunctional and finally trifunctional cross-links (8-10). The trifunctional cross-links derived from the hydroxyallysine route are referred to as pyridinolines. Collagens cross-linked by means of pyridinolines are difficult to degrade (11-13).The LH family consists of three individual members, designated LH1, LH2, and LH3. Hydroxylation of Lys present...

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“…Total collagen and elastin levels, as well as the abundance of the collagen cross-links dihydroxylysinonorleucine (DHLNL), hydroxylysylpiridinoline (HP), and hydroxylysinonorleucine (HLNL), and the elastin crosslinks desmosine and isodesmosine were determined exactly as described previously for adult mouse lungs and human tissues (10,48). The nomenclature used in this study refers to the reduced variants of the intermediate collagen cross-links (DHLNL, HLNL).…”

Section: Methodsmentioning

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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Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered cross-link pattern: Important pathogenetic steps in early and late stage of systemic scleroderma?

Cited by 61 publications

References 45 publications

Inflammation in intervertebral disc degeneration and regeneration

Inflammation in intervertebral disc degeneration and regeneration

Disentangling mechanisms involved in collagen pyridinoline cross-linking: The immunophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2

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

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