Constitutive Expression of Human Collagenase-3 (MMP-13) Induces Osteoarthritis-like Illness in Mice
An increasing body of evidence has pointed to a major role for matrix metalloproteinase (MMP-13) in the degradation of type II collagen in osteoarthritic (OA) cartilage. Neuhold et al (J Clin Invest 107:35, 2001) have expressed postnatally a constitutively active mutant of human collagenase-3 (MMP-13) in the articular cartilage of transgenic mice (through the use of a cartilage-specific promoter) in order to investigate its role in the pathogenesis of OA.
Transgenic mice were compared to wild type mice. The following were observed in the transgenic mice compared to wild type mice: 1) excessive cleavage of type II cartilage that correlated with enhanced expression of MMP-13; 2) loss of staining of safranin O, reflecting loss of proteoglycan aggrecan; 3) enhanced expression of type X collagen; 4) synovial hypertrophy but not inflammatory infiltrate. All of these changes mirror very closely the changes seen in human OA joints.
These data demonstrate that excessive activity of the proteinase MMP-13 can result in articular changes in transgenic mice that mimic human OA. It is unclear if the damage is all directly induced by MMP-13 or involves other processes.
Editorial Comment: These data further strengthen the rationale for developing a specific MMP-13 inhibitor for the treatment of human OA. Attempts to identify and develop MMP-13 inhibitors are in progress at several major pharmaceutical companies.
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