Complementary Roles of Intracellular and Pericellular Collagen Degradation Pathways In Vivo

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).