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.

SUPPLEMENTAL MATERIAL

We thank Mary Jo Danton for carefully reading the manuscript, Yanming Bi for help with computer tomography, and Ludmila Szobova for chondrocyte preparations.

This work was supported by the NIDCR Intramural Research Program and by a grant from the Department of Defense (DAMD-17-02-0693) to Thomas H. Bugge. Lars H. Engelholm and Niels Behrendt were supported by EU contract LSHC-CT-2003-503297 and by grants from the Danish Cancer Society, the Danish Cancer Research Foundation, and the Danish Medical Research Council.