Col6a1 null mice as a model to study skin phenotypes in patients with collagen VI related myopathies: expression of classical and novel collagen VI variants during wound healing.

Sandra Lettmann,Beate Eckes,Mats Paulsson,Jan-Niklas Schulz,Raimund Wagener,Anja Niehoff,Tobias Maaß,Wilhelm Bloch,Paolo Bonaldo,Sabine A Eming,Florence Ruggiero

doi:10.1371/journal.pone.0105686

Sandra Lettmann, Beate Eckes + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0105686

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Journal: PloS one	Publication Date: Aug 26, 2014
Citations: 40	License type: CC BY 4.0

Affiliation: University of Cologne, University of Padua

Abstract

Patients suffering from collagen VI related myopathies caused by mutations in COL6A1, COL6A2 and COL6A3 often also display skin abnormalities, like formation of keloids or “cigarette paper” scars, dry skin, striae rubrae and keratosis pilaris (follicular keratosis). Here we evaluated if Col6a1 null mice, an established animal model for the muscle changes in collagen VI related myopathies, are also suitable for the study of mechanisms leading to the skin pathology. We performed a comprehensive study of the expression of all six collagen VI chains in unwounded and challenged skin of wild type and Col6a1 null mice. Expression of collagen VI chains is regulated in both skin wounds and bleomycin-induced fibrosis and the collagen VI α3 chain is proteolytically processed in both wild type and Col6a1 null mice. Interestingly, we detected a decreased tensile strength of the skin and an altered collagen fibril and basement membrane architecture in Col6a1 null mice, the latter being features that are also found in collagen VI myopathy patients. Although Col6a1 null mice do not display an overt wound healing defect, these mice are a relevant animal model to study the skin pathology in collagen VI related disease.

Highlights

Mutations in COL6A1, COL6A2 and COL6A3 encoding collagen VI, cause Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy [1,2,3]
Expression of collagen VI chains is regulated in skin wounds and fibrosis To detect consequences of the lack of the collagen VI a1 chain on the expression of the classical a2 and a3 chains and the newly identified a4, a5, and a6 chains, we performed a comprehensive study of the distribution of the six collagen VI chains in wounds of wild type and Col6a1 null mice using chain-specific affinity purified antibodies
Analysis of cell culture media from Col6a1 null primary fibroblasts showed that some a3 chain was present as a single chain, indicating that a fraction the collagen VI a3 chains were secreted as individual molecules without forming heterotrimers (Fig. 2b)

Summary

Introduction

Mutations in COL6A1, COL6A2 and COL6A3 encoding collagen VI, cause Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy [1,2,3]. In addition to being a collagen it belongs to the superfamily of proteins containing von Willebrand factor A (VWA) domains [9], globular protein modules that act by mediating protein-protein interactions. Collagen VI was long considered to consist of three genetically distinct a-chains (a1, a2 and a3). These chains form heterotrimeric monomers that assemble into dimers and tetramers already in the cell [10,11]. Polymers are formed by end-to-end interactions of the pre-assembled tetramers, yielding the characteristic beaded filaments seen by electron microscopy [12,13]

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