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Molecular and Cellular Biology, September 2007, p. 6309-6322, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.00291-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Complementary Roles of Intracellular and Pericellular Collagen Degradation Pathways In Vivo{triangledown} ,{dagger}

Rebecca A. Wagenaar-Miller,1 Lars H. Engelholm,2 Julie Gavard,1 Susan S. Yamada,3 J. Silvio Gutkind,1 Niels Behrendt,2 Thomas H. Bugge,1* and Kenn Holmbeck3*

Oral and Pharyngeal Cancer Branch,1 Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, Maryland 20892,3 Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Ole Maalø Vej 5, DK-2200 Copenhagen N, Denmark2

Received 16 February 2007/ Returned for modification 10 April 2007/ Accepted 27 June 2007

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.

* Corresponding author. Mailing address for Thomas H. Bugge: Proteases and Tissue Remodeling Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 211, Bethesda, MD 20892. Phone: (301) 435-1840. Fax: (301) 402-0823. E-mail: thomas.bugge{at}nih.gov. Mailing address for Kenn Holmbeck: Matrix Metalloproteinases Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 125, Bethesda, MD 20892. Phone: (301) 496-3922. Fax: (301) 594-1253. E-mail: kenn.holmbeck{at}nih.gov

{triangledown} Published ahead of print on 9 July 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2007, p. 6309-6322, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.00291-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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