Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase

Abstract

The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin. Its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase (a major collagen cross-linking enzyme) and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Together, the data suggest a fibromodulin-modulated collagen cross-linking mechanism where fibromodulin binds to a specific part of the collagen domain and also forms a complex with lysyl oxidase, targeting the enzyme toward specific cross-linking sites.

The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

“…It is possible that an inability to mature the collagen fibrils results from disturbances in the enzyme arrays responsible for cross-link formation. Recently, we showed that fibromodulin interacts with Lox and can direct collagen cross-link formation (45). A decreased expression of fibromodulin can result in an impairment of fibril maturation even if Lox is increased, as it was observed in the current study in which the expression of Lox and Loxl2 were increased.…”

P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA

“…Further studies suggested that fibromodulin interacts with lysyl oxidase supporting this conclusion (23). Interestingly, the shift in band intensity in the current mice was most prominent in skin, less so in tendon, and absent in bone collagen extracts.…”

Collagen cross-linking: insights on the evolution of metazoan extracellular matrix

“…Although this study did not analyze the contribution of residues C-terminal to the reactive lysine, found to be highly conserved in our work, these observations reflect a higher degree of complexity in the recognition of collagen chains by LOX than that brought about by short peptides in solution. To this respect, LOX enzymes have been shown to be more active with collagen forming fibrils than with solubilized forms as a substrate, and more importantly, their binding capacity highly influenced by collagen-binding proteins such as small leucine-rich proteins (SRLP)111241. Closely linked to this, LOX enzymes are also responsible for the cross-linking of tropoelastin monomers during the process of formation of elastic fibers, and sequence recognition within the tropoelastin chain very much differs from that observed in collagens42.…”

“…In fact, defects in PLOD2, the lysyl hydroxylase isoform that specifically acts on lysine residues in collagen telopeptides, are responsible for Brück syndrome, a heritable disorder in the osteogenesis imperfecta spectrum, characterized by severe reduction or elimination of the telopeptide hydroxylysine-derived cross-links, resulting in bone fragility10. In addition to lysyl hydroxylases, collagen-associated proteins such as the small leucine-rich protein (SLRP), fibromodulin, have been shown to influence collagen cross-linking, as recently evidenced in fibromodulin-deficient mice1112.…”