Newly identified interfibrillar collagen crosslinking suppresses cell proliferation and remodelling

Abstract Copper is becoming recognised as a key cation in a variety of biological processes. Copper chelation has been studied as a potential anti-angiogenic strategy for arresting tumour growth. Conversely the delivery of copper ions and complexes in vivo can elicit a pro-angiogenic effect. Previou...

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Bibliographic Details
Published in:Biomaterials 2015-06, Vol.54, p.126-135
Main Authors: Marelli, Benedetto, Le Nihouannen, Damien, Hacking, S. Adam, Tran, Simon, Li, Jingjing, Murshed, Monzur, Doillon, Charles J, Ghezzi, Chiara E, Zhang, Yu Ling, Nazhat, Showan N, Barralet, Jake E
Format: Article
Language:English
Subjects:
Advanced Basic Science
Age
Biomedical materials
Bone
Cell Differentiation - physiology
Cell Proliferation - physiology
Cells, Cultured
Collagen
Collagens
Copper
Copper - chemistry
Copper - metabolism
Cross-Linking Reagents - chemistry
Cross-Linking Reagents - metabolism
Crosslinking
Dentistry
Deposition
Extracellular Matrix - chemistry
Extracellular Matrix - metabolism
Fibrillar Collagens - chemistry
Fibrillar Collagens - metabolism
Fibroblasts
Fibroblasts - cytology
Fibroblasts - physiology
Humans
Matrix Metalloproteinases - metabolism
Surgical implants
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Summary:Abstract Copper is becoming recognised as a key cation in a variety of biological processes. Copper chelation has been studied as a potential anti-angiogenic strategy for arresting tumour growth. Conversely the delivery of copper ions and complexes in vivo can elicit a pro-angiogenic effect. Previously we unexpectedly found that copper-stimulated intraperitoneal angiogenesis was accompanied by collagen deposition. Here, in hard tissue, not only was healing accelerated by copper, but again enhanced deposition of collagen was detected at 2 weeks. Experiments with reconstituted collagen showed that addition of copper ions post-fibrillogenesis rendered plastically-compressed gels resistant to collagenases, enhanced their mechanical properties and increased the denaturation temperature of the protein. Unexpectedly, this apparently interfibrillar crosslinking was not affected by addition of glucose or ascorbic acid, which are required for crosslinking by advanced glycation end products (AGEs). Fibroblasts cultured on copper-crosslinked gels did not proliferate, whereas those cultured with an equivalent quantity of copper on either tissue culture plastic or collagen showed no effect compared with controls. Although non-proliferative, fibroblasts grown on copper-cross-linked collagen could migrate, remained metabolically active for at least 14 days and displayed a 6-fold increase in Mmps 1 and 3 mRNA expression compared with copper-free controls. The ability of copper ions to crosslink collagen fibrils during densification and independently of AGEs or Fenton type reactions is previously unreported. The effect on MMP susceptibility of collagen and the dramatic change in cell behaviour on this crosslinked ECM may contribute to shedding some light on unexplained phenomena as the apparent benefit of copper complexation in fibrotic disorders or the enhanced collagen deposition in response to localised copper delivery.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2015.03.018