Biglycan as a modulator of fibrous connective tissue

Sammanfattning: Fibrous connective tissue contains fibroblasts distributed in a complex network of extracellular matrix molecules, such as proteoglycans. The small proteoglycans biglycan and decorin are composed of a protein core substituted with two and one glycosaminoglycan (GAG) chain, respectively. Proteoglycan metabolism is regulated differently during several processes including inflammation and wound healing. Proinflammatory cytokines, such as TNF-a and IL-1b, can affect matrix composition by increasing biglycan, versican and hyaluronan, and decreasing decorin and collagen. This results in a more loosely associated connective tissue that enhances the infiltration of inflammatory cells. Moreover, TNF-a can bind to both biglycan and decorin. In the inflammatory process, this may be of utmost importance since biglycan and decorin are located and regulated differently. The pericellular location of biglycan can enhance the binding of TNF-a to its cell surface receptors, while decorin, located in the extracellular matrix, may function as a storage depot. Besides the predominant form of biglycan, different isoforms can be secreted that possess a smaller core protein and greater diversity in the structure and length of their GAG chains. This variation in the structure of biglycan may alter its ability to bind cytokines as well as other matrix molecules potentially resulting in changes in the connective tissue formation. Biglycan and decorin also have important functions in the tissue repair process where they induce fibroblast cytoskeletal changes. These include morphological changes to a longer, stretched cell shape, formation of stress fibres and focal adhesions. These may be caused by an activation of the Rho GTPases, RhoA and Rac1, followed by an increase in migration. In summary, our results demonstrate that biglycan and decorin affect fibroblast activity and that they have a role both in physiological and pathological processes where the extracellular matrix is continuously being remodelled.