Morphogenesis, tissue remodeling, and tissue repair all require the targeted remodeling of interstitial and basement membrane collagen to allow for organ growth, cell migration, and translation of contextual cues that are embedded within the extracellular matrix. Perturbed collagen homeostasis underlies a remarkable array of important human diseases, including fibrosis, that are attributable to excess interstitial deposition of collagen and degenerative diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, which are characterized by a loss of collagen from tissues. Finally, the ability of tumor cells to leave their site of origin and seed at novel locations is dependent on their ability to orchestrate the local degradation of collagen (Joyce and Pollard, 2009; Rowe and Weiss, 2009; Kessenbrock et al., 2010). Understanding the precise mechanisms underlying normal and abnormal collagen homeostasis is, therefore, of significant basic biological and clinical importance. The mechanisms of collagen turnover have been the subject of extensive studies over the past several decades, and two mechanistically different collagen catabolic pathways have been proposed: an extracellular pathway, in which collagen is degraded by membrane-bound and soluble proteases, and an endocytic pathway, in which collagen is first internalized by cells and then