Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon

Slot, Annemarie J. Van Der; Zuurmond, A.-M.; Bogaerdt, Antoon J. van den; Ulrich, Magda M. W.; Middelkoop, Esther; Boers, W.; Ronday, H.K.; DeGroot, Jeroen; Huizinga, Tom W J; Bank, Ruud A.

doi:10.1016/j.matbio.2004.06.001

Cited by 191 publications

(184 citation statements)

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“…The substrate specificity of LH2a is unknown, but most likely not the telopeptides. A higher expression of LH2 has been reported in fibrosis (specifically: LH2b) 32, 33, 34, 36, explaining the higher level of pyridinoline cross‐links. How the expression of PLOD1 , PLOD2 and PLOD3 (encoding LH1, LH2 and LH3 respetively) is regulated is essentially unknown.…”

Section: Discussionmentioning

confidence: 91%

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Mia

Bank

2015

J Cellular Molecular Medi

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Excessive accumulation of a collagen‐rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFβ1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF‐κB) pathway by phosphorylating IκB with the enzyme IκB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2‐Amino‐6‐[2‐(cyclopropylmethoxy)‐6‐hydroxyphenyl]‐4‐(4‐piperidinyl)‐3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF‐κB pathway. It is not known whether ACHP has potential anti‐fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFβ1‐induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha‐smooth muscle actin (αSMA) and SM22α, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post‐treatment with ACHP partly reversed the expression of αSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen‐modifying enzymes lysyl hydroxylase (PLOD1,PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF‐κB pathway plays an important role in myofibroblast biology.

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Section: Discussionmentioning

confidence: 91%

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Mia

Bank

2015

J Cellular Molecular Medi

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“…To date, all lh2 mutations identified in Bruck syndrome, a disorder associated with decreased levels of telopeptidyl lysyl hydroxylase (TLH) activity, are predicted to affect both splice variants of this gene (Ha-Vinh et al, 2004;van der Slot et al, 2003). However, only increased levels of lh2b mRNA expression appear to be associated with increased levels of TLH activity found in fibrotic lesions, suggesting that the sequence of exon 13A encodes the LH2 domain responsible for specifying TLH activity (van der Slot et al, 2003;van der Slot et al, 2004).…”

Section: Analysis Of Lh2 Splice Variantsmentioning

confidence: 99%

“…However, only increased levels of lh2b mRNA expression appear to be associated with increased levels of TLH activity found in fibrotic lesions, suggesting that the sequence of exon 13A encodes the LH2 domain responsible for specifying TLH activity (van der Slot et al, 2003;van der Slot et al, 2004). We aligned the amino acid sequence encoded by exon 13A of zebrafish lh2 to that of other vertebrate species (obtained from GenBank) to identify residues whose evolutionary conservation might indicate their contribution to this activity ( Fig.…”

Section: Analysis Of Lh2 Splice Variantsmentioning

confidence: 99%

“…In humans, mutations in lh1 (also known as plod1) have been linked to Ehlers-Danlos (type VIA) syndrome, a recessive disorder characterized by hyperextendable skin, joint hypermobility and kyphoscoliosis (Yeowell and Walker, 2000). In contrast to LH1, LH2 also has telopeptidyl lysyl hydroxylase activity (van der Slot et al, 2003). Recently, mutations in human lh2 (plod2) were linked to Bruck syndrome, distinguished by fragile bones and contractures of the large joints (Ha-Vinh et al, 2004;van der Slot et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to LH1, LH2 also has telopeptidyl lysyl hydroxylase activity (van der Slot et al, 2003). Recently, mutations in human lh2 (plod2) were linked to Bruck syndrome, distinguished by fragile bones and contractures of the large joints (Ha-Vinh et al, 2004;van der Slot et al, 2003). LH3, in addition to exhibiting lysyl hydroxylase activity, is the only LH enzyme to possess additional glycosyltransferase activities that serve to further modify hydroxylysine residues to galactosylhydroxylysine and glucosylgalactosylhydroxylysine (Heikkinen et al, 2000;Rautavuoma et al, 2002;Wang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Genomic structure and embryonic expression of zebrafish lysyl hydroxylase 1 and lysyl hydroxylase 2

Schneider

Granato

2007

Matrix Biology

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Collagen biosynthesis in both invertebrates and vertebrates is critically dependent upon the activity of lysyl hydroxylase (LH) enzymes. In humans, mutations in the genes encoding LH1 and LH2 have been shown to cause two distinct connective tissue disorders, Ehlers-Danlos (Type VIA) and Bruck syndromes. While the biochemical properties of these enzymes have been intensively studied, their embryonic patterns of expression and developmental roles remain unknown. We now present the cloning and analyses of the genes encoding LH1 and LH2 in the zebrafish, Danio rerio. We find these genes to be similarly organized to other vertebrate lh (plod) genes, including the presence of an alternatively spliced exon in lh2. We also examine the mRNA expression patterns of lh1 and lh2 during embryogenesis and find them to exhibit unique and dynamic patterns of expression. These results strongly suggest that LH enzymes are not merely housekeeping enzymes, but play distinct developmental roles. The identification of these genes in the zebrafish, a genetic model organism whose development is well characterized, now provides the basis for the establishment of the first animal models for both Ehlers-Danlos (Type VIA) and Bruck syndromes.

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Epidemiology and Risk Factors for Pathologic Scarring After Burn Wounds

Gangemi

Gregori

Berchialla

et al. 2008

Archives of Facial Plastic Surgery

226

136

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To describe the clinical characteristics of postburn scars and determine the independent risk factors specific to these patients. While burns may generate widespread and disfiguring scars and have a dramatic influence on patient quality of life, the prevalence of postburn pathologic scarring is not well documented, and the impact of certain risk factors is poorly understood. Methods: A retrospective analysis was conducted of the clinical records of 703 patients (2440 anatomic burn sites) treated at the Turin Burn Outpatient Clinic between January 1994 and May 15, 2006. Prevalence and evolution time of postburn pathologic scarring were analyzed with univariate and multivariate risk factor analysis by sex, age, burn surface and full-thickness area, cause of the burn, wound healing time, type of burn treatment, number of surgical procedures, type of surgery, type of skin graft, and excision and graft timing. Results: Pathologic scarring was diagnosed in 540 patients (77%): 310 had hypertrophic scars (44%); 34, contractures (5%); and 196, hypertrophic-contracted scars (28%). The hypertrophic induction was assessed at a median of 23 days after reepithelialization and lasted 15 months (median). A nomogram, based on the multivariate regression model, showed that female sex, young age, burn sites on the neck and/or upper limbs, multiple surgical procedures, and meshed skin grafts were independent risk factors for postburn pathologic scarring (Dxy 0.30). Conclusion: The identification of the principal risk factors for postburn pathologic scarring not only would be a valuable aid in early risk stratification but also might help in assessing outcomes adjusted for patient risk.

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Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon

Cited by 191 publications

References 35 publications

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Genomic structure and embryonic expression of zebrafish lysyl hydroxylase 1 and lysyl hydroxylase 2

Epidemiology and Risk Factors for Pathologic Scarring After Burn Wounds

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