Collagens are expressed in various types of cells, but principally by fibroblasts.  The newly formed collagen is formed as a soluble protein so that it can pass out through the cell membrane, but once expressed it must undergo post-translational processing in the extracellular space.   Like all soluble proteins, the nascent collagen has an amino-terminus and a carboxyl-terminus, but in order for the collagen segment to become part on an insoluble extracellular matrix, it is necessary to remove these termini.

Once the termini have been cleaved, the tropocollagen segments will self-assemble to form the characteristic triple-helical structure of collagen fibers, and these fibers are what make up the extracellular matrix.  The carboxyl terminus, or C-terminus, has a different morphology than the amino terminus, or N-terminus, and presence of an intact C-terminus prevents collagen self-assembly while a collagen protein with an incompletely cleaved N-terminus can still be incorporated into the collagen trimer.  Incomplete cleavage of the C-terminus can lead to a number of pathologies including Ehlers-Danlos Syndrome and Osteogenesis Imperfecta.

The image is a scanning electron micrograph of normal and "barbed wire" collagen morphologies.  When collagen is fully processed and both termini are removed, the resulting collagen has an evenly spaced structure with 67 nm fibrils as shown in the left panel.  When cleavage of the C-terminus is inhibited, the collagen fibrils cannot self-assemble resulting in a disorganized pattern as shown in the right panel.

There are a number of hypertrophic scarring disorders that result from excessive collagen deposition including keloid scarring and burns.  The collagen contained in these scars begins as Type III collagen, but remodels over time into Type I scar.  Type I is a high tensile strength form of collagen found in bones and connective tissues, such as tendons, that is resistant to metalloproteinases, naturally occurring enzymes that degrade old tissue as part of the normal tissue remodeling process.

Our small molecule inhibitor of PCP is orally available, which may be a useful treatment for systemic scleroderma, and the molecule can be incorporated into a topical ointment or gel that can be applied directly to hypertrophic scars to convert consolidated Type I scar to the barbed wire morphology necessary for tissue remodeling to resolve the scar.