Fibulin-2 and fibulin-5 alterations in tsk mice associated with disorganized hypodermal elastic fibers and skin tethering.

The Tight skin (Tsk) mouse is an important model of skin fibrosis that occurs in systemic sclerosis. These mice develop skin tethering and thickening associated with expression of a mutant fibrillin-1 gene. We show that Tsk fibrillin-1 leads to marked alterations in elastic fibers of the hypodermis of Tsk animals. In Tsk mice, a prominent elastic fiber layer found normally at the interface between hypodermal muscle and connective tissue was absent from an early age. The lack of elastic fibers at the hypodermal muscle-connective tissue (M-CT) interface was associated with a loss of staining for fibulin-5 in the same region. These mice also formed disorganized elastic fibers throughout hypodermal connective tissue as they aged. The increased elastic fibers in Tsk hypodermal connective tissue was associated with increased fibrillin-1 and fibulin-2 matrices. These results suggest that Tsk fibrillin-1 causes skin tethering by altering matrix protein composition in Tsk hypodermal connective tissues. The closely parallel alterations in elastogenesis associated with increased fibulin-2 in hypodermal connective tissues and decreased fibulin-5 at the hypodermal M-CT interface suggest that these proteins mediate the effect of Tsk-fibrillin-1 on elastogenesis.