Selective enhancement of collagenase-mediated cleavage of resident type IIcollagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1)

Objective. To examine whether type II collagen cleavage by collagenase and loss of proteoglycan are excessive in human osteoarthritic (OA) articular c artilage compared with nonarthritic articular cartilage, and whether this c an be inhibited by a selective synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1 [MMP-1]). Methods. Articular cartilage samples were obtained during surgery from 11 p atients with OA and at autopsy from 5 adults without arthritis. The articul ar cartilage samples were cultured in serum-free medium. A collagenase-gene rated neoepitope, which reflects cleavage of type II collagen, and proteogl ycan glycosaminoglycan (GAG), which predominantly reflects aggrecan release , were assayed in culture media. In addition, cultures were performed using either of 2 synthetic MMP inhibitors, both of which inhibited collagenase 2 (MMP-8) and collagenase 3 (MMP-13), but one of which spared collagenase 1 , Cultures were also biolabeled with H-3-proline in the presence and absenc e of these inhibitors to measure collagen synthesis las tritiated hydroxypr oline) and incorporation in articular cartilage. Results. As a group, cleavage of type II collagen by collagenase was signif icantly increased in OA cartilage samples. In contrast, proteoglycan (GAG) release was not increased. This release of a collagenase-generated epitope was inhibited by both MMP inhibitors in 2 of 5 nonarthritic samples and in 9 of 11 OA cartilage samples. The inhibitor that spared collagenase 1 was g enerally more effective and inhibited release from 4 of 5 nonarthritic cart ilage samples and the same OA cartilage samples. Group analyses revealed th at the inhibition of collagenase neoepitope release by both inhibitors was significant in the OA patient cartilage, but not in the nonarthritic cartil age. Proteoglycan loss was unaffected by either inhibitor. Newly synthesize d collagen (predominantly, type II) exhibited increased incorporation in OA cartilage, but only in the presence of the inhibitor that arrested collage nase 1 activity. Conclusion. These results further indicate that the digestion of type II co llagen by collagenase is selectively increased in OA cartilage, and that th is can be inhibited in the majority of cases by a synthetic inhibitor that can inhibit collagenases 2 and 3, but not collagenase 1, The results also s uggest that in OA, newly synthesized collagen is digested, but in a differe nt manner than that of resident molecules. Proteoglycan release was not inc reased in OA cartilage and was unaffected by these inhibitors. Inhibitors o f this kind may be of value in preventing damage to type II collagen in hum an arthritic articular cartilage.