uPARAP/Endo180-dependent intracellular collagen degradation a major pathway of pathophysiological collagen turnover.

WAGENAAR-MILLER R.A.; CURINO A. C.; ENGELHOLM L.H.; BOYE SCHNACK- NIELSEN B.; KJOLLER L.; MOLINOLO A.; HOLMBECK K.; BEHRENDT N.; BUGGE T.H.

Anaheim/Orange County, CA, USA.

Congreso; American Association for Cancer Research (AACR) annual meeting.; 2005

American Association for Cancer Research (AACR)

uPARAP/Endo180-dependent intracellular collagen degradation - a major pathway of pathophysiological collagen turnover. Rebecca A. Wagenaar-Miller, Alejandro C. Curino, Lars H. Engelholm, Boye S. Nielsen, Lars Kjøller, Alfredo A. Molinolo, Kenn Holmbeck, Niels Behrendt, Thomas H. Bugge. NIH-NIDCR, Bethesda, MD, Finsen Laboratory, Copenhagen University Hospital, Copenhagen, Denmark. The urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 is a member of the macrophage mannose receptor family of recycling endocytic transmembrane glycoproteins. uPARAP/Endo180 is a 180 kDa multidomain glycoprotein that consists of an N-terminal cysteine-rich domain, a collagen binding fibronectin type II domain, eight C-type carbohydrate recognition domains, a transmembrane domain, and a short C-terminal cytoplasmic tail. In situ hybridization and immunohistochemical studies reveal that uPARAP/Endo180 is expressed at low levels in homeostatic tissues. However, uPARAP/Endo180 is abundantly expressed by mesenchymal cells located at sites of active tissue remodeling and rapid extracellular matrix turnover. This includes both physiological tissue remodeling (odontogenesis, endochondral and intramembranous ossification) and pathophysiological tissue remodeling (tumor invasion), where uPARAP/Endo180 is found on chondrocytes, fibroblasts, macrophages, myofibroblasts, odontoblasts, osteoblasts, and osteocytes.Surprisingly, genetic ablation of uPARAP/Endo180 leads to a specific and near complete abrogation of the ability of mesenchymal cells to internalize and degrade a range of collagen species. This defect is apparent in both cultured uPARAP/Endo180-deficient fibroblasts and in fibroblast-like cells within primary explants of uPARAP/Endo180-deficient Polyoma virus middle T-induced mammary tumors. This novel uPARAP/Endo180-dependent intracellular collagen degradation pathway is critical to collagen turnover during tumor progression, as evidenced by accumulation of interstitial collagen and impaired growth of Polyoma virus middle T-induced mammary tumors in uPARAP/Endo180-deficient mice. uPARAP/Endo180 expression is conspicuously similar to the major fibrillar collagenase, MT1-MMP. Indeed, preliminary studies suggest that combined deficits in uPARAP/Endo180-dependent intracellular and MT1-MMP-dependent extracellular collagen degradation pathways are incompatible with prolonged postnatal survival of mice.Taken together, these studies identify uPARAP/Endo180-mediated intracellular degradation of collagen as a major pathway for the turnover of this abundant extracellular matrix component within both pathological and physiological contexts.