Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development.
OBJECTIVE
To investigate the role of matrix metalloproteinase 13 (MMP-13; collagenase 3) in osteoarthritis (OA).


METHODS
OA was surgically induced in the knees of MMP-13-knockout mice and wild-type mice, and mice were compared. Histologic scoring of femoral and tibial cartilage aggrecan loss (0-3 scale), erosion (0-7 scale), and chondrocyte hypertrophy (0-1 scale), as well as osteophyte size (0-3 scale) and maturity (0-3 scale) was performed. Serial sections were stained for type X collagen and the MMP-generated aggrecan neoepitope DIPEN.


RESULTS
Following surgery, aggrecan loss and cartilage erosion were more severe in the tibia than femur (P<0.01) and tibial cartilage erosion increased with time (P<0.05) in wild-type mice. Cartilaginous osteophytes were present at 4 weeks and underwent ossification, with size and maturity increasing by 8 weeks (P<0.01). There was no difference between genotypes in aggrecan loss or cartilage erosion at 4 weeks. There was less tibial cartilage erosion in knockout mice than in wild-type mice at 8 weeks (P<0.02). Cartilaginous osteophytes were larger in knockout mice at 4 weeks (P<0.01), but by 8 weeks osteophyte maturity and size were no different from those in wild-type mice. Articular chondrocyte hypertrophy with positive type X collagen and DIPEN staining occurred in both wild-type and knockout mouse joints.


CONCLUSIONS
Our findings indicate that structural cartilage damage in a mouse model of OA is dependent on MMP-13 activity. Chondrocyte hypertrophy is not regulated by MMP-13 activity in this model and does not in itself lead to cartilage erosion. MMP-13 deficiency can inhibit cartilage erosion in the presence of aggrecan depletion, supporting the potential for therapeutic intervention in established OA with MMP-13 inhibitors.
Little
C B
CB
Raymond Purves Research Laboratories, University of Sydney at Royal North Shore Hospital, St. Leonard's, New South Wales, Australia. cblittle@med.usyd.edu.au
Barai
A
A
Burkhardt
D
D
Smith
S M
SM
Fosang
A J
AJ
Werb
Z
Z
Shah
M
M
Thompson
E W
EW
D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002114:Calcinosis / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology*; D019902:Chondrocytes / Q000473:pathology*; D005269:Femur / Q000473:pathology; D006984:Hypertrophy; D007596:Joints / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054850:Osteophyte / Q000473:pathology; D013977:Tibia / Q000473:pathology
D053674:Aggrecans; D053509:Matrix Metalloproteinase 13