Aggrecan protects cartilage collagen from proteolytic cleavage.
The matrix components responsible for cartilage mechanical properties, type II collagen and aggrecan, are degraded in osteoarthritis through proteolytic cleavage by matrix metalloproteinases (MMPs) and aggrecanases, respectively. We now show that aggrecan may serve to protect cartilage collagen from degradation. Although collagen in freeze-thawed cartilage depleted of aggrecan was completely degraded following incubation with MMP-1, collagen in cartilage with intact aggrecan was not. Using interleukin-1-stimulated bovine nasal cartilage explants where aggrecan depletion occurs during the first week of culture, followed by collagen loss during the second week, we evaluated the effect of selective MMP and aggrecanase inhibitors on degradation. A selective MMP inhibitor did not block aggrecan degradation but caused complete inhibition of collagen breakdown. Similar inhibition was seen with inhibitor addition following aggrecan depletion on day 6-8, suggesting that MMPs are not causing significant collagen degradation prior to the second week of culture. Inclusion of a selective aggrecanase inhibitor blocked aggrecan degradation, and, in addition, inhibited collagen degradation. When the inhibitor was introduced following aggrecan depletion, it had no effect on collagen breakdown, ruling out a direct effect through inhibition of collagenase. These data suggest that aggrecan plays a protective role in preventing degradation of collagen fibrils, and that an aggrecanase inhibitor may impart overall cartilage protection.
Pratta
Michael A
MA
Bristol Myers-Squibb Pharmaceutical Company, Wilmington, Delaware 19898, USA. michael_a_pratta@gsk.com
Yao
Wenqing
W
Decicco
Carl
C
Tortorella
Micky D
MD
Liu
Riu-Qin
RQ
Copeland
Robert A
RA
Magolda
Ronald
R
Newton
Robert C
RC
Trzaskos
James M
JM
Arner
Elizabeth C
EC
D053674:Aggrecans; D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000378:metabolism; D037181:Lectins, C-Type; D008954:Models, Biological; D008956:Models, Chemical; D011509:Proteoglycans / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D053674:Aggrecans; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D011509:Proteoglycans; D003094:Collagen