[Frontiers in Bioscience 11, 3081 -3095, September 1, 2006]

The role of collagenolytic matrix metalloproteinases in the loss of articular cartilage in osteoarthritis

Gerald N. Smith, Jr.

Department of Medicine, Division of Rheumatology, Indiana University School of Medicine, Indianapolis, Indiana

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Collagens of cartilage ECM
4. The collagenolytic MMPs
5. Control of MMP activity
5.1. Control of MMP expression
5.2. Endogenous MMP inhibitors
5.3. Activation of latent MMPs
6. Evidence that MMP digest collagen in OA cartilage
6.1. MMPs are able to digest cartilage collagen
6.2. MMP expression is increased in OA cartilage
6.3. OA cartilage contains MMP digestion products
6.4. Changing MMP activity changes OA progression
6.4.1. Genetic alteration of MMP expression
6.4.2. Pharmacologic inhibition of MMP activity
6.4.3. Pharmacologic inhibition of MMP expression
7. Conclusions and caveats
8. Acknowledgements
9. References

1. ABSTRACT

Digestion of cartilage collagen is a critical step in the loss of articular cartilage in osteoarthritis (OA). The hypothesis that matrix metalloproteinases (MMPs) are the primary enzymes involved in cartilage collagen digestion is supported by evidence that indicates that: 1) one or more MMP can digest the extracellular matrix components in vitro, 2) the enzymes are expressed in OA cartilage at the place and time of cartilage destruction, 3) specific digestion products of MMP are present in the OA cartilage, and 4) experimental strategies that alter the expression and/or the activity of MMP alter the progression of cartilage destruction in OA. These observations suggest that MMPs in general and collagenolytic MMPs in particular are promising targets for treatment of OA.