MATRIX METALLOPROTEINASE-13 DEFICIENT MICE ARE RESISTANT TO OSTEOARTHRITIC CARTILAGE EROSION BUT NOT CHONDROCYTE HYPERTROPHY OR OSTEOPHYTE DEVELOPMENT

By C. Little, A. Barai, D. Burkhardt, Susan M. Smith, A. Fosang, Zena Werb, M. Shah, E. Thompson. Arthritis & Rheumatism, 2009

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Objectives To investigate the role of matrix metalloproteinase (MMP)-13/collagenase-3 in osteoarthritis (OA). Methods Surgically-induced OA in knees of MMP-13 knock out (KO) and wild type (WT) mice was compared. Femoral and tibial cartilage aggrecan loss (0–3), erosion (0–7) and chondrocyte hypertrophy (0–1), as well as osteophyte size (0–3) and maturity (0–3) were histologically scored. Serial sections were stained for collagen type X and the MMP-generated aggrecan neo-epitope 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 WT 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. Tibial cartilage erosion in KO mice was less than WT at 8 weeks (p<0.02). Cartilaginous osteophytes were larger in KO at 4 weeks (p<0.01), but by 8 weeks osteophyte maturity and size were no different from WT. Articular chondrocyte hypertrophy with positive type X collagen and DIPEN staining occurred in both WT and KO joints. Conclusions These studies have confirmed that structural cartilage damage in mouse experimental 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.

Subfields: Cancer Research, Rheumatology, Surgery

View Paper: https://www.semanticscholar.org/paper/f8db7dc8e4852cfcda1f696923b17d6a494ea896

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