Complementary Roles of Intracellular and Pericellular Collagen Degradation Pathways In Vivo

Abstract

Collagen degradation is essential for cell migration, proliferation, and differentiation. Two key turnover pathways have been described for collagen: intracellular cathepsin-mediated degradation and pericellular collagenase-mediated degradation. However, the functional relationship between these two pathways is unclear and even controversial. Here we show that intracellular and pericellular collagen turnover pathways have complementary roles in vivo. Individual deficits in intracellular collagen degradation (urokinase plasminogen activator receptor-associated protein/Endo180 ablation) or pericellular collagen degradation (membrane type 1-matrix metalloproteinase ablation) were compatible with development and survival. Their combined deficits, however, synergized to cause postnatal death by severely impairing bone formation. Interestingly, this was mechanistically linked to the proliferative failure and poor survival of cartilage-and bone-forming cells within their collagen-rich microenvironment. These findings have important implications for the use of pharmacological inhibitors of collagenase activity to prevent connective tissue destruction in a variety of diseases.The collagens are the most abundant extracellular matrix components in the body and can constitute as much as 90% of the extracellular matrix of a tissue. They consist of three polypeptide chains, each with a single long, uninterrupted section of Gly-X-Y amino acid repeats that are intertwined to produce a superhelix that buries the peptide bonds within the interior of the helix. The fibrillar collagens spontaneously selfassociate to form fibrils that range in diameter from 10 to 300 nm, while basement membrane collagens form complicated sheets with both triple-helical and globular motifs (26,39).Extensive turnover of collagen takes place during a variety of physiological and pathological tissue-remodeling processes, including development, tissue repair, degenerative connective tissue diseases, and cancer. In this context, collagen turnover serves at least five different functions. It facilitates the physical expansion of a tissue (normal or aberrant), liberates latent growth factors embedded within the extracellular matrix, enables vascular development, subverts the proliferative restrictions imposed on cells by the extracellular matrix, and directly regulates cellular differentiation (5, 22, 30). Inhibition of extracellular matrix degradation, therefore, has long been recognized as an attractive target for therapeutic intervention in a variety of human diseases (1, 6).Three molecular pathways are known for the turnover of collagen in physiological and pathological tissue-remodeling processes. The best-studied pathway involves a group of secreted or membrane-associated matrix metalloproteinases, the collagenases, that directly cleave collagens within the pericellular or extracellular environment (4, 44). A second, cathepsin K-mediated pathway is specific for osteoclast-mediated bone resorption and takes place in the acidic microenvironment that is ...

Altered Chondrocyte Differentiation and Extracellular Matrix Homeostasis in a Zebrafish Model for Mucolipidosis II

“…The turnover of collagen within developing bone and cartilage begins with its initial proteolysis within the pericellular space by a group of secreted or membrane-associated matrix metalloproteinases. 47,48 Complete turnover may either be completed outside the cell by the action of gelatinases such as metalloproteinase-2 or following endocytosis of defined fragments into the cell, transport to lysosomes, and proteolytic degradation of acid-denatured collagen by cathepsins. Loss of the cathepsin proteases from the lysosomes, a common feature in some ML-II cell types, may therefore result in failure to fully degrade type II collagen and other ECM proteins via the intracellular pathway.…”

Membrane type-1 matrix metalloproteinase activity is regulated by the endocytic collagen receptor Endo180

“…Studies to date have focused on how MT1-MMP-mediated limited fragmentation of collagen might influence uptake by Endo180 (Madsen et al, 2007;Wagenaar-Miller et al, 2007). By contrast, here we have explored whether Endo180 can regulate protease activity and thus direct pericellular collagen proteolysis.…”

Cell-Protein-Material Interaction in Tissue Engineering

“…For example, the state of collagen polymerization has been shown to alter its growth regulatory properties (Schofield, 1978). Emerging evidence also indicates that the ECM form of FN (matrix fibrils) is functionally distinct from the soluble FN (Hynes, 1990;Wagenaar-Mller et al, 2007), having implications on the long-term behaviour of this protein. Thus, depending on the allowance of materials surface to support the development of fibrillar matrix, the biological properties of a material may be altered.…”

“…These processes are mostly active during development and regeneration of tissues but, when miss-regulated, can contribute to diseases. Perturbing matrix remodelling, for example by preventing the turnover of collagen type I or altering the level of matrix-degrading proteases, has been shown to result in fibrosis, arthritis, reduced angiogenesis, and developmental abnormalities (Schofield, 1978;Wagenaar-Mller et al, 2007;Heyman et al, 2006;Holmbeck et al, 1999). The invasive behaviour of cancer cells is also due to up-regulation of matrix remodelling (Reisenawer et al, 2007;Carino et al, 2005).…”