“MMP-13 inhibitors might be useful in halting cartilage erosion in osteoarthritis,” claims Christopher Little, Director of the Raymond Purves Bone and Joint Research Laboratories, The University of Sydney at The Royal North Shore Hospital, Australia, based on research from his lab now published in Arthritis & Rheumatism.

Articular cartilage erosion is a characteristic feature of osteoarthritis (OA) and, at present, no drugs that inhibit this process are available. Erosion results from breakdown of cartilage components, including aggrecan (caused by a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTS] enzymes), the collagen network (caused by matrix metalloproteinases [MMPs]) and extracellular matrix proteins.

“A great deal of work has already been published using cell and tissue culture suggesting the importance of MMP-13 in collagenolysis, but what was unclear was whether inhibiting this enzyme alone could reduce or stop cartilage loss in OA,” explains Little.

... Mmp13 knockout mice showed significant inhibition of cartilage erosion in OA...

The researchers compared the progression of surgically induced OA (by medial meniscal destabilization) in wild-type and Mmp13−/− mice, which were previously generated by Stickens et al.and described as having altered endochondral bone development, which normalized by 12 weeks of age. “As Mmp13 knockout mice appear to be normal once they reach maturity, and in the case of our research interests so do their joints, they provide an ideal in vivo model system to answer questions about the role of MMP-13 in OA.”

At 4 weeks after induction of OA levels of aggrecan loss and cartilage erosion were similar in wild-type and Mmp13−/− mice; however, at 8 weeks, despite a considerable increase in aggrecan loss in the Mmp13−/− mice in comparison with wild-type mice, tibial cartilage erosion was significantly lower in the knockout mice than in the wild-type animals (P <0.02). The authors also assessed osteophyte development and chondrocyte hypertrophy in the two groups of mice: at 8 weeks post-surgery they found no differences between the wild-type and knockout animals.

“The most important finding was that Mmp13 knockout mice showed significant inhibition of cartilage erosion in OA,” says Little. His group are now interested in assessing whether inhibiting cartilage erosion in OA could help reduce the pain and disability that are such important clinical aspects of this disease. “Given that there was little effect of MMP-13 abrogation on joint pathology other than cartilage erosion in this model, we plan to investigate whether there is any evidence of altered pain in Mmp13 knockout versus wild-type mice.”

As the researchers discuss in the paper, how transferable these results obtained using a mouse model are to human disease is unclear at this stage and further studies are needed.