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.Progressive erosion of articular cartilage is a significant determinant of prognosis and the need for joint replacement surgery in osteoarthritis (OA). Proteolysis of the principal NIH Public Access Author ManuscriptArthritis Rheum. Author manuscript; available in PMC 2010 December 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cartilage extracellular matrix constituents, aggrecan and the type II/IX/XI collagen network, directly causes erosion as well as predisposing the tissue to mechanical disruption even with loading at physiological levels. Aggrecan proteolysis and loss precedes and may be prerequisite for subsequent collagenolysis (1). A distintegrin and metalloproteinase with thrombospondin repeat (ADAMTS) enzymes are responsible for pathological aggrecanolysis (2,3). ADAMTS-5 is the predominant arthritis-associated enzyme in mice, since animals deficient in ADAMTS-5 activity are protected from cartilage erosion in OA and inflammatory arthritis (4-6). Ablating the ADAMTS cleavage site in the interglobular domain of aggrecan also blocks cartilage structural damage, confirming that the effect in ADAMTS-5-deficient mice is due to inhibition of aggrecanolysis (7).The above studies demonstrate that inhibiting the initiation of aggrecan loss can prevent subsequent structural cartilage damage/erosion in arthritis. Clinically, it is likely that e...

Male MRL/MpJ mice appear to possess an intrinsic ability to 'regenerate' articular cartilage. Understanding the biochemical and genetic basis for articular cartilage regeneration may open up new treatment options for traumatic articular cartilage defects.

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Osteoarthritis (OA) is a highly prevalent joint disease. Its slow progressive nature and the correlation between pathological changes and clinical symptoms mean that OA is often well advanced by the time of diagnosis. In the absence of any specific pharmacological treatments, there is a pressing need to develop robust biomarkers for OA. We have adopted a nuclear magnetic resonance (NMR)-based metabolomic strategy to identify molecular responses to surgically induced OA in an animal model. Sheep underwent one of three types of surgical procedure (sham (control), meniscal destabilization, MD or anterior cruciate ligament transaction, ACLT), and for every animal a serum sample was collected both pre- and postoperatively, thus, affording two types of "control" data for comparison. 1D 1H NMR spectra were acquired from each sample at 800 MHz and the digitized spectral data were analyzed using principal components analysis and partial least-squares regression discriminant analysis. Our approach, combined with the study design, allowed us to separate the metabolic responses to surgical intervention from those associated with OA. We were able to identify dimethyl sulfone (DMSO2) as being increased in MD after 4 weeks, while ACLT-induced OA exhibited increased 3-methylhistidine and decreased branched chain amino acids (BCAAs). The findings are discussed in the context of interpretation of metabolomic results in studies of human disease, and the selection of appropriate "control" data sets.