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Inhibition of collagen fibril formation.

Steplewski A, Fertala A - Fibrogenesis Tissue Repair (2012)

Bottom Line: The overall aim of presented study is to test the inhibition of the formation of collagen fibrils as the novel approach to reduce accumulation of pathological fibrotic deposits.The main hypothesis is that by interfering with the initial steps of the extracellular process of collagen fibril formation, it is possible to reduce the formation of fibrotic tissue.The experimental model includes antibody-based inhibitors that specifically bind to the sites that participate in the collagen/collagen interaction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedic Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

ABSTRACT

Background: The overall aim of presented study is to test the inhibition of the formation of collagen fibrils as the novel approach to reduce accumulation of pathological fibrotic deposits. The main hypothesis is that by interfering with the initial steps of the extracellular process of collagen fibril formation, it is possible to reduce the formation of fibrotic tissue.

Methods: The experimental model includes antibody-based inhibitors that specifically bind to the sites that participate in the collagen/collagen interaction.

Results: Employed antibody-based inhibitors effectively limit the amount of collagen fibrils formed in vitro and in engineered tissue models of localized fibrosis.

Conclusions: (i) Inhibition of collagen formation is an attractive target to reduce excessive formation of fibrotic tissue. (ii) Antibody-based inhibitors of collagen fibril formation are promising therapeutic agents with a potential to limit localized fibrosis in a number of tissues.

No MeSH data available.


Related in: MedlinePlus

Collagen/collagen interaction sites involved in fibril formation; the basic concept of inhibiting collagen fibril formation. A, the stages of normal fibril formation by site-specific interaction between telopeptides of one collagen molecule and the T-TBR of the interacting molecule located in the D4 period; fibril-incorporated collagen molecules are very resistant to enzymatic degradation. B, by blocking the sites of critical collagen-collagen interaction, formation of fibrils is inhibited, preventing the accumulation of fibrils and allowing rapid degradation of excess collagen molecules. Asterisks represent sites of cross-links formation. The model of a microfibril illustrates the compact packing of collagen molecules (indicated in colors matching those for specific D periods) and indicates how the binding of a bulky inhibitor to collagen molecules would prevent such a compact organization.
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Figure 3: Collagen/collagen interaction sites involved in fibril formation; the basic concept of inhibiting collagen fibril formation. A, the stages of normal fibril formation by site-specific interaction between telopeptides of one collagen molecule and the T-TBR of the interacting molecule located in the D4 period; fibril-incorporated collagen molecules are very resistant to enzymatic degradation. B, by blocking the sites of critical collagen-collagen interaction, formation of fibrils is inhibited, preventing the accumulation of fibrils and allowing rapid degradation of excess collagen molecules. Asterisks represent sites of cross-links formation. The model of a microfibril illustrates the compact packing of collagen molecules (indicated in colors matching those for specific D periods) and indicates how the binding of a bulky inhibitor to collagen molecules would prevent such a compact organization.

Mentions: Collagen I is the most abundant structural protein of connective tissues such as skin, bone, and tendon. This protein is first synthesized as a precursor molecule, procollagen, that is characterized by the presence of a rod-like central triple-helical domain flanked by short linear telopeptides and globular N-terminal and C-terminal propeptides [1]. Single procollagen molecules are the building blocks for the biologically-and mechanically-relevant collagen fibrils (Figure 1). The formation of collagen fibrils is initiated by enzymatic cleavage of N-terminal and C-terminal propeptides. The N-terminal propeptides are cleaved by a group of enzymes that includes a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-2, -3, and -14, while the C-terminal propeptides are processed by the metalloprotease bone morphogenetic protein 1 (BMP-1) and by the other members of a closely related family of mammalian tolloid-like metalloproteases [2-4]. Such removal of procollagen propeptides exposes telopeptides, which drive collagen self-assembly by engaging in site-specific intermolecular interactions [5] (Figure 1, Figure 2, and Figure 3A).


Inhibition of collagen fibril formation.

Steplewski A, Fertala A - Fibrogenesis Tissue Repair (2012)

Collagen/collagen interaction sites involved in fibril formation; the basic concept of inhibiting collagen fibril formation. A, the stages of normal fibril formation by site-specific interaction between telopeptides of one collagen molecule and the T-TBR of the interacting molecule located in the D4 period; fibril-incorporated collagen molecules are very resistant to enzymatic degradation. B, by blocking the sites of critical collagen-collagen interaction, formation of fibrils is inhibited, preventing the accumulation of fibrils and allowing rapid degradation of excess collagen molecules. Asterisks represent sites of cross-links formation. The model of a microfibril illustrates the compact packing of collagen molecules (indicated in colors matching those for specific D periods) and indicates how the binding of a bulky inhibitor to collagen molecules would prevent such a compact organization.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368754&req=5

Figure 3: Collagen/collagen interaction sites involved in fibril formation; the basic concept of inhibiting collagen fibril formation. A, the stages of normal fibril formation by site-specific interaction between telopeptides of one collagen molecule and the T-TBR of the interacting molecule located in the D4 period; fibril-incorporated collagen molecules are very resistant to enzymatic degradation. B, by blocking the sites of critical collagen-collagen interaction, formation of fibrils is inhibited, preventing the accumulation of fibrils and allowing rapid degradation of excess collagen molecules. Asterisks represent sites of cross-links formation. The model of a microfibril illustrates the compact packing of collagen molecules (indicated in colors matching those for specific D periods) and indicates how the binding of a bulky inhibitor to collagen molecules would prevent such a compact organization.
Mentions: Collagen I is the most abundant structural protein of connective tissues such as skin, bone, and tendon. This protein is first synthesized as a precursor molecule, procollagen, that is characterized by the presence of a rod-like central triple-helical domain flanked by short linear telopeptides and globular N-terminal and C-terminal propeptides [1]. Single procollagen molecules are the building blocks for the biologically-and mechanically-relevant collagen fibrils (Figure 1). The formation of collagen fibrils is initiated by enzymatic cleavage of N-terminal and C-terminal propeptides. The N-terminal propeptides are cleaved by a group of enzymes that includes a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-2, -3, and -14, while the C-terminal propeptides are processed by the metalloprotease bone morphogenetic protein 1 (BMP-1) and by the other members of a closely related family of mammalian tolloid-like metalloproteases [2-4]. Such removal of procollagen propeptides exposes telopeptides, which drive collagen self-assembly by engaging in site-specific intermolecular interactions [5] (Figure 1, Figure 2, and Figure 3A).

Bottom Line: The overall aim of presented study is to test the inhibition of the formation of collagen fibrils as the novel approach to reduce accumulation of pathological fibrotic deposits.The main hypothesis is that by interfering with the initial steps of the extracellular process of collagen fibril formation, it is possible to reduce the formation of fibrotic tissue.The experimental model includes antibody-based inhibitors that specifically bind to the sites that participate in the collagen/collagen interaction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedic Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

ABSTRACT

Background: The overall aim of presented study is to test the inhibition of the formation of collagen fibrils as the novel approach to reduce accumulation of pathological fibrotic deposits. The main hypothesis is that by interfering with the initial steps of the extracellular process of collagen fibril formation, it is possible to reduce the formation of fibrotic tissue.

Methods: The experimental model includes antibody-based inhibitors that specifically bind to the sites that participate in the collagen/collagen interaction.

Results: Employed antibody-based inhibitors effectively limit the amount of collagen fibrils formed in vitro and in engineered tissue models of localized fibrosis.

Conclusions: (i) Inhibition of collagen formation is an attractive target to reduce excessive formation of fibrotic tissue. (ii) Antibody-based inhibitors of collagen fibril formation are promising therapeutic agents with a potential to limit localized fibrosis in a number of tissues.

No MeSH data available.


Related in: MedlinePlus