The roles of collagen XVIII and its endostatin domain in wound healing, hair follicle cycling and bone development
University of Oulu, Faculty of Medicine, Institute of Biomedicine, Department of Medical Biochemistry and Molecular Biology
University of Oulu, Biocenter Oulu
University of Oulu, Center for Cell Matrix Research
Kokoteksti (PDF, 1 MB)
Academic dissertation to be presented with the assent of the Faculty of Medicine of the University of Oulu for public defence in Auditorium 275F of the Department of Pharmacology and Toxicology (Aapistie 5), on 4 December 2009, at 12 noon
|Tarkastaja(t):|| Docent Marja Mikkola
Doctor Orlando Musso
Collagen XVIII is a basement membrane proteoglycan, which has three variant N-termini. These variants are coded by two promoters; promoter 1 directs the synthesis of a short variant and promoter 2 directs the synthesis of two longer variants, of which the middle variant is generated from the longest by splicing. The longest variant contains a cysteine-rich domain in its N-terminus, which shows homology to the frizzled receptors of the Wnt molecules and can inhibit Wnt/beta-catenin signalling in vitro. The C-terminal domain of collagen XVIII, endostatin, is an inhibitor of tumor growth and angiogenesis.
Lack of collagen XVIII accelerates cutanous wound healing and wound angiogenesis. Overexpression of endostatin leads to delayed wound healing and the presence of morphologically abnormal wound capillaries. Moreover, endostatin overexpression leads to delayed formation of the wound epidermal basement membrane and impaired maturation of hemidesmosomes.
Endostatin treatment decreases osteoblast proliferation in vitro. Moreover, osteoblast proliferation and mineralization of the matrix by osteoblasts are inhibited when cells are treated with endostatin together with VEGF. In vivo, lack of collagen XVIII leads to delayed formation of secondary ossification centers in mouse femurs, whereas overexpression of endostatin leads to a slower growth of bone length. However, both of these changes are transient and mild, suggesting that collagen XVIII/endostatin is not essential for skeletal development.
The growth of hair follicles is delayed in the mice overexpressing endostatin. This delay in growth is preceded by an impaired hair follicle associated angiogenesis. Lack of collagen XVIII causes an accelerated onset of the first hair cycle. A similar change can be seen in mice lacking the long variants of collagen XVIII. Lack of the short variant causes mild acceleration in the catagen of the first cycle, and anagen is also significantly accelerated in these mice. The long variants were located in the bulge region, which contains the hair follicle stem cells, and in the basement membrane surrounding the dermal papilla. As it is known that several Wnt-inhibitors are upregulated in the bulge, our results suggest that the longest variant of collagen XVIII may have a role as a regulator of Wnt-signalling in hair follicles.
Acta Universitatis Ouluensis. Series D, Medica
|ISBN Print:|| 978-951-42-6063-6
collagen type XVIII
|Tekijänoikeustiedot:||Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.|