Expression in SPARC-null mice of collagen type I lacking the globular domain of the α1(I) N-propeptide results in abdominal hernias and loss of dermal collagen.
The sequence encoding the N-propeptide of collagen I is characterized by significant conservation of amino acids across species; however, the function of the N-propeptide remains poorly defined. Studies in vitro have suggested that one activity of this propeptide might be to act as a feedback inhibitor of collagen I synthesis. To determine whether the N-propeptide contributed to decreased collagen content in SPARC-null mice, mice carrying a deletion of exon 2, which encodes the globular domain of the N-propeptide of collagen I, were crossed to SPARC-null animals. Mice lacking SPARC and expressing collagen I without the globular domain of the N-propeptide were viable and fertile. However, a significant number of animals developed abdominal hernias within the first 2 months of life with an approximate 20% penetrance (~35% of males). The dermis of SPARC-null/exon 2-deleted mice was thinner and contained fewer large collagen fibers in comparison with wild-type or in either single transgenic animal. The average collagen fibril diameter of exon 2-deleted mice did not significantly differ from wild-type mice (WT: 87.9 nm versus exon 2-deleted: 88.2 nm), whereas SPARC-null/exon 2-deleted fibrils were smaller than that of SPARC-null dermis (SPARC-null: 60.2 nm, SPARC-null/exon 2-deleted: 40.8 nm). As measured by hydroxyproline analysis, double transgenic skin biopsies contained significantly less collagen than those of wild-type, those of exon 2-deleted, and those of SPARC-null biopsies. Acetic acid extraction of collagen from skin biopsies revealed an increase in the proportion of soluble collagen in the SPARC-null/exon 2-deleted mice. These results support a function of the N-propeptide of collagen I in facilitating incorporation and stabilization of collagen I into the insoluble ECM and argue against a primary function of the N-propeptide as a negative regulator of collagen synthesis.
Card
Lauren
L
Gazes Cardiac Research Institute, Division of Cardiology, Dept. of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States.
Henderson
Nikki
N
Zhang
Yuhua
Y
Bornstein
Paul
P
Bradshaw
Amy D
AD
D000818:Animals; D003094:Collagen / Q000032:analysis / Q000378:metabolism* / Q000648:ultrastructure; D024042:Collagen Type I / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D020405:Dermis / Q000002:abnormalities* / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D005091:Exons / Q000235:genetics; D005109:Extracellular Matrix / Q000737:chemistry; D017353:Gene Deletion; D046449:Hernia, Abdominal / Q000235:genetics* / Q000473:pathology; D006909:Hydroxyproline / Q000032:analysis; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009026:Mortality; D015676:Osteonectin / Q000235:genetics*; D010641:Phenotype; D010748:Phosphopeptides / Q000235:genetics*; D011347:Procollagen / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C062121:N-propeptide type I collagen; D015676:Osteonectin; D010748:Phosphopeptides; D011347:Procollagen; D003094:Collagen; D006909:Hydroxyproline