Effects of elevated circulating IGF-1 on the extracellular matrix in "high-growth" C57BL/6J mice

Collagen biosynthesis was analyzed in C57BL/6J mice homozygous for the high-growth locus. Plasma levels of insulin-like growth factor-1 (IGF-1) were significantly elevated in high-growth mice at all ages studied (3 wk-6 mo); IGF-binding proteins were also elevated. Skin biopsies were obtained from mice aged 3, 6, and 9 wk under halothane anesthesia. Mice were killed at 6 mo of age. Collagen, expressed per weight of tissue, was significantly increased in all tissues from high-growth mice, as was collagen cross-linking, expressed as moles of cross-link per mole of collagen. Expression of types I and III collagen, lysyl oxidase, and lysyl hydroxylase was increased in all tissues analyzed. There was a preferential increase in type III expression relative to type I expression. Rate and extent of accumulation of collagen in granulation tissue were measured in polyvinyl alcohol sponges implanted subcutaneously; collagen accumulation was significantly greater in the high-growth mice. These results suggest that 1) elevated circulating IGF-1 may increase collagen deposition both in normal tissue as well as in granulation tissue by increasing collagen gene expression, 2) IGF-1 may increase collagen cross-linking by stimulating expression of lysyl oxidase, and 3) the preferential increase in dihydroxylated cross-links observed in high-growth mice may be due to the stimulation of lysyl hydroxylase expression by IGF-1. In summary, elevated levels of IGF-1 appear to affect collagen both quantitatively and qualitatively, primarily through their effects on gene expression of collagen and of those enzymes responsible for posttranslational modifications of collagen.

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Lysyl hydroxylase gene expression and collagen cross-linking in normal, acute hepatic failure and cirrhotic human liver

Gastroenterology ◽

10.1016/s0016-5085(00)86098-9 ◽

2000 ◽

Vol 118 (4) ◽

pp. A988

Author(s):

Sung-Kyu Choi ◽

Mitsuo Yamauchi ◽

Branko Stefanovic ◽

David A. Brenner

Keyword(s):

Gene Expression ◽

Hepatic Failure ◽

Human Liver ◽

Acute Hepatic Failure ◽

Cross Linking ◽

Lysyl Hydroxylase ◽

Hydroxylase Gene ◽

Collagen Cross Linking

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Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: Implications for collagen cross-linking and treatment of fibrosis

Matrix Biology ◽

10.1016/j.matbio.2005.04.002 ◽

2005 ◽

Vol 24 (4) ◽

pp. 261-270 ◽

Cited By ~ 23

Author(s):

A ZUURMOND ◽

A VANDERSLOTVERHOEVEN ◽

E VANDURA ◽

J DEGROOT ◽

R BANK

Keyword(s):

Gene Expression ◽

Cross Linking ◽

Inhibitory Effects ◽

Lysyl Hydroxylase ◽

Lysyl Hydroxylase 1 ◽

Collagen Cross Linking

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Collagen cross-linking. Synthesis of collagen cross-links in vitro with highly purified lysyl oxidase.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)33124-1 ◽

1976 ◽

Vol 251 (18) ◽

pp. 5786-5792

Author(s):

R C Siegel

Keyword(s):

Lysyl Oxidase ◽

Cross Linking ◽

Cross Links ◽

Collagen Cross Linking

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Modulation of lysyl oxidase activity toward peptidyl lysine by vicinal dicarboxylic amino acid residues. Implications for collagen cross-linking.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)31798-2 ◽

1994 ◽

Vol 269 (35) ◽

pp. 22366-22371 ◽

Cited By ~ 1

Author(s):

N. Nagan ◽

H.M. Kagan

Keyword(s):

Amino Acid ◽

Oxidase Activity ◽

Lysyl Oxidase ◽

Cross Linking ◽

Amino Acid Residues ◽

Dicarboxylic Amino Acid ◽

Collagen Cross Linking

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Abstract 17388: Loss of Bone Morphogenetic Protein 9 (BMP9) Limits Survival and Paradoxically Increases Collagen Abundance, but Limits Collagen Cross-Linking in a Murine Model of Acute Myocardial Infarction

Circulation ◽

10.1161/circ.142.suppl_3.17388 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Shreyas Bhave ◽

Michele Esposito ◽

Lija Swain ◽

Xiaoying QIAO ◽

Gregory Martin ◽

...

Keyword(s):

Myocardial Infarction ◽

Bone Morphogenetic Protein ◽

Murine Model ◽

Cardiac Remodeling ◽

Type I Collagen ◽

Cross Linking ◽

Type I ◽

Morphogenetic Protein ◽

Bone Morphogenetic Protein 9 ◽

Collagen Cross Linking

Myocardial infarction (MI) is a major cause of heart failure (HF). HF is associated with adverse cardiac remodeling that is primarily driven by Transforming growth factor beta (TGFb1) mediated fibrosis and myocyte hypertrophy. We previously reported that loss of bone morphogenetic protein 9 (BMP9) promotes cardiac fibrosis in pressure-overload induced HF. No studies have explored a role for BMP9 in post MI cardiac remodeling. We hypothesize that loss of BMP9 may promote cardiac healing by stabilizing LV scar formation. To test this hypothesis, we subjected whole body BMP9 knockout (-/-) mice to left coronary artery ligation for two weeks followed by PV loop analysis and studied indices of cardiac remodeling. Compared to wild type (WT) controls BMP9-/- mice had significantly lower survival (83% vs 61%, p<0.001, respectively) with a higher rate of cardiac rupture(15% vs 90%). Compared to WT controls, surviving BMP9-/- mice had higher LVEDP, reduced LV dP/dt, and higher lung weight. Compared to WT mice, BMP9-/- mice had significantly higher levels of Type I collagen (2 fold p<0.05). Compared to WT mice, BMP9-/- mice had increased matrix metalloproteinases (MMP)-2 and MMP-9 (2.5 fold p<0.05) activity levels in the LV. Treatment of cultured primary human cardiac fibroblasts with recombinant BMP9 attenuated TGFb1-mediated Type I collagen and MMP-9 protein expression. To assess collagen content and cross-linking, two-photon excitation fluorescence imaging was performed and identified an increase in collagen abundance, but a trend towards lower collagen cross-linking in the LV of BMP9-/- mice compared to WT mice 2 weeks after MI. Our central finding is that loss of BMP9 is associated with reduced survival, increased propensity towards cardiac rupture, and increased LV collagen abundance, but reduced collagen integrity in a murine model of acute MI. These identify a potentially important functional role for BMP9 in post-infarct cardiac remodeling.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1600074113 ◽

2016 ◽

Vol 113 (26) ◽

pp. 7142-7147 ◽

Cited By ~ 33

Author(s):

Rutger A. F. Gjaltema ◽

Miesje M. van der Stoel ◽

Miriam Boersema ◽

Ruud A. Bank

Keyword(s):

Posttranslational Modifications ◽

Molecular Level ◽

Splice Variants ◽

Active Form ◽

Connective Tissue Disorder ◽

Cross Linking ◽

Ppiase Activity ◽

Lysyl Hydroxylase ◽

Bruck Syndrome ◽

Lysine Hydroxylation

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.

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