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.
| Original language | English |
|---|---|
| Journal | Molecular and Cellular Biology |
| Volume | 27 |
| Issue number | 18 |
| Pages (from-to) | 6309-22 |
| Number of pages | 14 |
| ISSN | 0270-7306 |
| DOIs | |
| Publication status | Published - Sept 2007 |
Keywords
- Alleles
- Animals
- Animals, Newborn
- Bone Density
- Cells, Cultured
- Chondrocytes
- Collagen
- Eosine Yellowish-(YS)
- Hematoxylin
- Immunohistochemistry
- In Situ Hybridization
- Matrix Metalloproteinase 14
- Mice
- Mice, Congenic
- Mice, Inbred Strains
- Mice, Knockout
- Osteoblasts
- Osteogenesis
- Receptors, Cell Surface
- Receptors, Mitogen
- Receptors, Urokinase Plasminogen Activator
- Skull
- Tomography, X-Ray Computed
- Journal Article
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.