Matrix metalloproteinases are not essential for aggrecan turnover during normal skeletal growth and development.
The growth plate is a transitional region of cartilage and highly diversified chondrocytes that controls long bone formation. The composition of growth plate cartilage changes markedly from the epiphysis to the metaphysis, notably with the loss of type II collagen, concomitant with an increase in MMP-13; type X collagen; and the C-propeptide of type II collagen. In contrast, the fate of aggrecan in the growth plate is not clear: there is biosynthesis and loss of aggrecan from hypertrophic cartilage, but the mechanism of loss is unknown. All matrix metalloproteinases (MMPs) cleave aggrecan between amino acids N341 and F342 in the proteinase-sensitive interglobular domain (IGD), and MMPs in the growth plate are thought to have a role in aggrecanolysis. We have generated mice with aggrecan resistant to proteolysis by MMPs in the IGD and found that the mice develop normally with no skeletal deformities. The mutant mice do not accumulate aggrecan, and there is no significant compensatory proteolysis occurring at alternate sites in the IGD. Our studies reveal that MMP cleavage in this key region is not a predominant mechanism for removing aggrecan from growth plate cartilage.
Little
Christopher B
CB
Arthritis Research Group, University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville 3052, Australia.
Meeker
Clare T
CT
Hembry
Rosalind M
RM
Sims
Natalie A
NA
Lawlor
Kate E
KE
Golub
Sue B
SB
Last
Karena
K
Fosang
Amanda J
AJ
D053674:Aggrecans; D019943:Amino Acid Substitution; D000818:Animals; D001846:Bone Development / Q000502:physiology*; D001842:Bone and Bones / Q000033:anatomy & histology / Q000378:metabolism; D017364:Collagenases / Q000235:genetics / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006132:Growth Plate / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D037181:Lectins, C-Type; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000235:genetics; D011509:Proteoglycans / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012863:Skeleton
C508320:Acan protein, mouse; D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507081:Mmp13 protein, mouse