title: Analysis of the tight skin (Tsk1/+) mouse as a model for testing antifibrotic agents.
abstract: The tight skin 1 (B6.CgFbn1(Tsk)+/+Pldn(pa)/J, henceforth referred to as Tsk1/+) mouse was first described as a spontaneously occurring mutant that resulted in hyperplasia of the subcutaneous loose connective tissue, and has subsequently been proposed to be a model of the human fibrotic disorder scleroderma. We have investigated the Tsk1/+ mouse as a model system for testing the efficacy of antifibrotic agents against skin fibrosis. We find that the tightness of the skin at the scruff of the neck leads to a measurably thicker skin pinch, but we suggest that this is due to hyperplasia of the subdermal loose connective tissue, which results in increased tethering of the skin to the underlying muscle layers. In contrast to previously published data, we do not find a significant difference in the dermal thickness or collagen content of the Tsk1/+ mouse skin compared with wild-type controls. In addition, expression profiling of Tsk1/+ mouse skin indicated that there are very few changes in gene expression, and that there is no evidence for upregulation of the transforming growth factor beta signaling axis. Therefore, we conclude that this model is not suitable for testing the effect of antifibrotic agents on the dermis, and that changes potentially related to scleroderma may be confined to subdermal connective tissue.
authors.affiliation: Department of Research Pathology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Baxter
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Crowell
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCrann
authors.forename: Erica M
authors.initials: EM
authors.lastname: Frew
authors.forename: Humphrey
authors.initials: H
authors.lastname: Gardner
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000071837:Fibrillins; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012737:Sex Factors; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C475219:Tsk1 protein, mouse; D003094:Collagen; D017346:Protein Serine-Threonine Kinases