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.
Wagenaar-Miller
Rebecca A
RA
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 211, Bethesda, MD 20892, USA.
Engelholm
Lars H
LH
Gavard
Julie
J
Yamada
Susan S
SS
Gutkind
J Silvio
JS
Behrendt
Niels
N
Bugge
Thomas H
TH
Holmbeck
Kenn
K
D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D003094:Collagen / Q000032:analysis / Q000145:classification* / Q000378:metabolism*; D004801:Eosine Yellowish-(YS) / Q000378:metabolism; D006416:Hematoxylin / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D012886:Skull / Q000166:cytology; D014057:Tomography, X-Ray Computed
C408294:Endo180; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D011975:Receptors, Mitogen; D055293:Receptors, Urokinase Plasminogen Activator; D003094:Collagen; D053511:Matrix Metalloproteinase 14; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin