Matrix Metalloproteinase 13-deficient Mice Are Resistant to Osteoarthritic Cartilage Erosion but Not Chondrocyte Hypertrophy or Osteophyte Development

Arthritis Rheum. 2009 Dec;60(12):3723-33. doi: 10.1002/art.25002.

Abstract

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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggrecans / metabolism
  • Animals
  • Arthritis, Experimental / enzymology*
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / pathology
  • Calcinosis / pathology
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology*
  • Chondrocytes / pathology*
  • Femur / pathology
  • Hypertrophy
  • Joints / metabolism
  • Joints / pathology
  • Joints / surgery
  • Male
  • Matrix Metalloproteinase 13 / deficiency*
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Mice
  • Mice, Knockout
  • Osteoarthritis / enzymology*
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology
  • Osteophyte / pathology
  • Tibia / pathology

Substances

  • Aggrecans
  • Matrix Metalloproteinase 13