The role of leucine-rich repeat glycoproteins/proteoglycans in the assembly of collagen matrices

University dissertation from Dept of Cell and Molecular Biology, Lund University

Abstract: The properties of different connective tissues depend on the synthesis and assembly of macromolecular structures composed of collagen and other extracellular matrix components. Mechanisms modulating these events play important roles in the formation of a functional tissue. We have studied the role of collagen-binding extracellular matrix leucine-rich repeat glycoproteins/proteoglycans in the formation of collagen matrices. A region in decorin with high affinity for collagen type I was identified. Using a mammalian cell expression system we produced recombinant chimeric proteoglycans consisting of decorin sequences fused with biglycan sequences. Biglycan is closely related to decorin but does not bind to collagen type I. The collagen-binding properties of the proteoglycans and the proteoglycan chimeras were investigated in collagen fibril formation/sedimentation assays. The chimeric proteoglycan consisting of biglycan, substituted with leucine-rich repeats 4-5 from decorin, bound collagen type I. This region represents 13% of the amino acid sequence of decorin and contains a major collagen binding site. To study the function of fibromodulin in vivo, a mouse strain lacking the expression of this proteoglycan was generated by gene targeting. These mice phenotypically showed abnormal collagen fibrils in tendons, suggesting a role for fibromodulin in collagen fibrillogenesis. Moreover, these fibromodulin-null mice showed an increased lumican deposition in tendons. Using both recombinant fibromodulin and lumican in collagen fibril formation/sedimentation assays, we showed that fibromodulin and the closely related lumican share a binding region on collagen type I fibrils. The binding of fibromodulin to collagen occurs with higher affinity than the binding of lumican.

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