Carbohydrates are thought to function as tags that mark circulatory glycoproteins for rapid clearance. To examine the role of the mannose receptor (MR) in glycoprotein clearance, we generated mice genetically deficient in MR. MR-/- mice were defective in clearing proteins bearing accessible mannose and N-acetylglucosamine residues and had elevated levels of eight different lysosomal hydrolases. Proteomic analysis of MR-/- and control mouse sera showed that an additional 4 out of 52 proteins identified were elevated in MR-/- serum. Each of these is up-regulated during inflammation and wound healing. Thus, MR appears to operate as an essential regulator of serum glycoprotein homeostasis.

We have studied the role of collagen receptors, integrins ␣ 11 ␤ 1 and ␣ 2 ␤ 1 , and fibronectin in collagen polymerization using fibronectin-deficient mouse embryonic fibroblast cell lines. In contrast to the earlier belief that collagen polymerization occurs via self-assembly of collagen molecules we show that a preformed fibronectin matrix is essential for collagen network formation and that collagen-binding integrins strongly enhance this process. Thus, collagen deposition is regulated by the cells, both indirectly through integrin ␣ 5 ␤ 1 -dependent polymerization of fibronectin and directly through collagenbinding integrins.Collagens form a large family of proteins with more than 20 different members described to date (3). The organization of different collagens into various types of fibrils and networks in extracellular matrices (ECM) 1 is of crucial importance for the physical properties of tissues. Type I and III collagens, the predominant proteins in the body, are prototypes for the fibrillar collagen subfamily. Although these collagens are known to serve as a scaffold for numerous associated proteins, proteoglycans, and cells in the ECM, the mechanisms that regulate their own polymerization are poorly understood.As all collagens, types I and III are composed of three ␣ chains that form triple-helical domains. The collagen triplehelices are assembled intracellularly in a process dependent on ascorbic acid as a cofactor for hydroxylation of selected prolines and lysines (4). In addition to the triple-helical region, procollagen molecules of type I and III collagens contain a propeptide in both the N-and C-terminal ends as well as the so-called telopeptides. In connection with secretion of the monomers into the extracellular space, the propeptides are usually removed by proteolytic cleavage. Removal of C-terminal propeptides is a prerequisite for the fibrillogenesis. For instance the ␣1(I) collagen chain, where the C-propeptide cleavage site was mutated, could not be incorporated into the fibrillar cross-linked collagen matrix (5). The fate of the N-terminal propeptides varies between the different collagens. Although it is efficiently removed from type I collagen, the N-terminal propeptide of type III collagen appears to be a normal constituent of the interstitial ECM (6 -8). The exact way by which type III procollagen is processed, the size of the pool of the N-propeptide that is not removed in different tissues, and its function(s) are currently not known. In contrast to the propeptides, the C-and N-terminal telopeptides of secreted mature collagen molecules are fully retained. The telopeptides, as well as the N-terminal propeptide of type III procollagen, serve as good antigenic markers due to their unique collagen type-specific sequences.Type I and III collagens isolated from tissues can polymerize in vitro, and therefore the fibrillogenesis in tissues has been thought to occur in a similar way via self-assembly guided by precise interactions between collagen molecules followed by organization of ...

Bone resorption may generate collagen fragments such as ICTP and CTX, which can be quantified in serum and/or urine by using specific immunoassays, and which are used as clinical markers. However, the relative abundance of ICTP and CTX varies according to the type of bone pathology, suggesting that these two fragments are generated through distinct collagenolytic pathways. In this study, we analyzed the release of ICTP and CTX from bone collagen by the proteinases reported to play a role in the solubilization of bone matrix. Cathepsin K released large amounts of CTX, but did not allow a detectable release of ICTP. Conversely, the matrix metalloproteinases (

Carcinoma cell invasion is traditionally studied in three-dimensional organotypic models composed of type I collagen and fibroblasts. However, carcinoma cell behavior is affected by the various cell types and the extracellular matrix (ECM) in the tumor microenvironment. In this study, a novel organotypic model based on human uterine leiomyoma tissue was established and characterized to create a more authentic environment for carcinoma cells. Human tongue squamous cell carcinoma cells (HSC-3) were cultured on top of either collagen or myoma. Organotypic sections were examined by immunohistochemistry and in situ hybridization. The maximal invasion depth of HSC-3 cells was markedly increased in myomas compared with collagen. In myomas, various cell types and ECM components were present, and the HSC-3 cells only expressed ECM molecules in the myoma model. Organotypic media were analyzed by radioimmunoassay, zymography, or Western blotting. During carcinoma cell invasion, matrix metalloprotease-9 production and collagen degradation were enhanced particularly in the myoma model. To evaluate the general applicability of the myoma model , several oral carcinoma , breast carcinoma , and melanoma cell lines were cultured on myomas and found to invade in highly distinct patterns. We conclude that myoma tissue mimics the native tumor microenvironment better than previous organotypic models and possibly enhances epithelial-tomesenchymal transition. Thus, the myoma model provides a promising tool for analyzing the behavior of carcinoma cells.