Overexpression of Lysyl Hydroxylase-2b Leads to Defective Collagen Fibrillogenesis and Matrix Mineralization

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

doi:10.1359/jbmr.2005.20.1.81

Cited by 7 publications

(4 citation statements)

References 39 publications

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“…12 Furthermore, LH2b expression could be induced in dermal fibroblasts by profibrotic cytokines such as TGF-b. 11 LH2b also had an effect on collagen fibril formation; over-expression of LH2b in MC3T3-E1 cells resulted in defective collagen fibrillogenesis 20 and led to a decreased fibril diameter. Moreover, collagen fibrils formed in the presence of LH2b were shown to be less susceptible to MMP degradation.…”

Section: Discussionmentioning

confidence: 96%

Expression profile of proteins involved in scar formation in the healing process of full‐thickness excisional wounds in the porcine model

Ulrich

Verkerk

Reijnen

et al. 2007

Wound Repair Regeneration

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Scar formation in deep dermal wounds is associated with excessive collagen deposition and contraction. Increased collagen synthesis and decreased collagen degradation are the mechanisms through which this form of fibrosis can occur. Another factor might be a different kind of collagen cross-linking seen in fibrotic skin diseases. This type of cross-linking is dependent on the enzyme lysyl hydroxylase-2b. In this study, we examined the expression profile of the potential key players in scar formation in time in healing of acute wounds. Collagen types I and III, lysyl hydroxylase-2b, alpha-smooth muscle actin, transforming growth factor betas, and the matrix metalloproteinases and their inhibitor mRNA levels were determined. All genes examined show distinct expression patterns over time. The expression of lysyl hydroxylase-2b peaks at day 7, and precedes collagen types I and III expression. Eight weeks after wounding, the scars showed an increased level of lysyl hydroxylase-2b-mediated collagen cross-linking. This study shows that the fibrosis-specific type of cross-linking of collagen seen in human hypertrophic scarring also plays a role in this animal model of wound healing. Moreover, the expression of the putative gene responsible for this type of cross-linking, the lysyl hydroxylase-2b, is elevated during wound healing.

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Section: Discussionmentioning

confidence: 96%

Expression profile of proteins involved in scar formation in the healing process of full‐thickness excisional wounds in the porcine model

Ulrich

Verkerk

Reijnen

et al. 2007

Wound Repair Regeneration

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“…There are several ways in which this may occur. First, over-hydroxylation of telopeptidyl lysine residues has been shown to interfere with collagen fibrillogenesis, resulting in smaller diameter collagen fibrils (Pornprasertsuk et al 2005). Increased lysine hydroxylation favours the formation of HL-Pyr rather than pyrrole cross-links.…”

Section: Discussionmentioning

confidence: 99%

Mechanical properties of the equine superficial digital flexor tendon relate to specific collagen cross‐link levels

Thorpe

Stark

Goodship

et al. 2010

Equine Veterinary Journal

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Reasons for performing study: Damage to the flexor tendons, particularly the superficial digital flexor tendon (SDFT), is one of the most common musculoskeletal injuries sustained by horses competing in all disciplines. Our previous work has shown that SDFTs from different individuals show a wide variation in mechanical strengths; this is important clinically as it may relate to predisposition to injury. The high mechanical strength of tendon relies on the correct orientation of collagen molecules within fibrils and stabilisation by the formation of chemical cross-links between collagen molecules. It is not known whether the variation in SDFT mechanical properties between individuals relates to differences in collagen cross-link levels. Hypothesis: Enzyme-derived, intermolecular cross-linking of tendon collagen correlates with mechanical properties of the SDFT. Methods: SDFTs were collected from 38 horses and mechanically tested to failure. Structural and material properties were calculated from the load/deformation plot and cross-sectional area for each tendon. Following mechanical testing, pyrrolic cross-link levels were measured using a spectrophotometric assay for Ehrlich's reactivity and pyridinoline levels were quantified by HPLC. Cross-link levels were correlated with mechanical properties and statistical significance tested using a Pearson's correlation test. Results: Pyrrole cross-link levels showed a significant positive correlation with ultimate stress (P = 0.004), yield stress (P = 0.003) and elastic modulus (P = 0.018) of the tendons, despite being a minor cross-link in these tendons. There was no significant correlation of mechanical properties with either hydroxylysyl-or lysyl-pyridinoline levels. Conclusions: Given the low absolute levels of pyrrole, we suggest that the correlation with high mechanical strength is through an indirect mechanism. Understanding the nature of the relationships between pyrrole cross-links, other matrix characteristics and tendon material properties may allow development of strategies to identify horses at risk from tendon injury and be of value in informing training practices.

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“…19 Increased plod2 expression leads to increased post-translational collagen cross-linking, resulting in reduced tensile strength. [20][21][22] The detrimental effects of increased collagen cross-linking have been identified in the weakened aortic wall present in Marfan syndrome and abdominal aortic aneurysms. 22 Disrupted post-translational collagen processing in the infarct zone may therefore underlie infarct expansion and ventricular dilatation observed following MI in the absence of eosinophils.…”

Section: Eosinophils Are Recruited To the Heart And Activated Followimentioning

confidence: 99%

Eosinophil deficiency promotes aberrant repair and adverse remodelling following acute myocardial infarction

Toor

Rückerl

Mair

et al. 2019

Preprint

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Background: Eosinophil count predicts outcome following myocardial infarction (MI) and eosinophils regulate tissue repair and regeneration in extra-cardiac settings.Objectives: To investigate the role of eosinophils in regulating inflammation, repair and remodelling following MI.Methods: Blood eosinophil count was assessed in 732 patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI (STEMI). Experimental MI was induced in wild-type (WT) and eosinophil-depleted mice (ΔdblGATA or anti-Siglec F antibody treated). Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of infarct digests. Results:Blood eosinophil count declined in the hours following STEMI in patients and following MI induction in mice. Eosinophils were subsequently identified in the myocardium of patients and mice. Genetic eosinophil depletion in mice increased LV dilatation (end-systolic area: 29.0±2.2cm 2 v 21.6±1.6cm 2 ; p=0.02) and reduced ejection fraction (22.0±3.6% v 34.3±4.0% in p=0.04,) in Δ dblGATA v WT following MI (n=8-9/group), an outcome reproduced by pharmacological depletion. Δ dblGATA mice had increased scar size with disrupted collagen deposition and altered expression of the collagen cross-linking genes plod2 and lox. CD206 + pro-repair macrophages were less prevalent in the infarct zone of Δ dblGATA mice (27.0±2.3% v WT: 39.2.4±3.5%; p=0.01, n=9-11/group) but were restored by replenishment with bone marrow-derived eosinophils. Anti-inflammatory cytokine concentrations were reduced in Δ dblGATA mice and IL-4 complex administration 24h after MI rescued adverse remodelling. Conclusions:Eosinophils are recruited to the heart following MI and are required for effective repair and to prevent adverse remodelling. IL-4 therapy has potential to limit detrimental outcomes when eosinophil availability is low. Condensed abstractIn ST-segment elevation myocardial infarction (STEMI) of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory pro-repair macrophage polarization, enhanced myocardial inflammation, increased scar size and deterioration of myocardial structure and function. Adverse cardiac remodelling in the setting of eosinophil deficiency was prevented by IL-4 therapy.

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Overexpression of Lysyl Hydroxylase-2b Leads to Defective Collagen Fibrillogenesis and Matrix Mineralization

Cited by 7 publications

References 39 publications

Expression profile of proteins involved in scar formation in the healing process of full‐thickness excisional wounds in the porcine model

Expression profile of proteins involved in scar formation in the healing process of full‐thickness excisional wounds in the porcine model

Mechanical properties of the equine superficial digital flexor tendon relate to specific collagen cross‐link levels

Eosinophil deficiency promotes aberrant repair and adverse remodelling following acute myocardial infarction

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