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The Journal of Bone and Joint Surgery (American) 83:826-838 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.

Immunolocalization of Matrix Metalloproteinases in Partial-Thickness Defects in Pig Articular Cartilage

A Preliminary Report

Rosalind M. Hembry, BSc, PhD, Jonathan Dyce, MA, VetMB, DSAO, MRCVS, Iris Driesang, DVM, Ernst B. Hunziker, MD, ME, Amanda J. Fosang, BSc, PhD, Jenny A. Tyler, BSc, PhD and Gillian Murphy, BSc, PhD

Investigation performed at the School of Biological Sciences, University of East Anglia, Norwich, United Kingdom
Rosalind M. Hembry, BSc, PhD
Gillian Murphy, BSc, PhD
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom. E-mail address for R.M. Hembry: r.hembry{at}uea.ac.uk

Jonathan Dyce, MA, VetMB, DSAO, MRCVS
College of Veterinary Medicine, Ohio State University, 601 Vernon L. Tharp Street, Columbus, OH 43210-1089

Iris Driesang, DVM
Ernst B. Hunziker, MD, ME
M.E. Müller Institute for Biomechanics, University of Bern, Murtenstrasse 35, P.O. Box 30, CH-3010 Bern, Switzerland

Amanda J. Fosang, BSc, PhD
University of Melbourne, Department of Paediatrics, Cell and Matrix Biology Research Unit and Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria 3052, Australia

Jenny A. Tyler, BSc, PhD
Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom

Although none of the authors has received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article, benefits have been or will be received but are directed solely to a research fund, foundation, educational institution, or other nonprofit organization with which one or more of the authors is associated. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were the Medical Research Council (United Kingdom) and Orthogene (Sausalito, California).

Background: Partial-thickness defects in mature articular cartilage do not heal spontaneously. Attempts at repair often result in limited integration between the repair tissue and the surrounding cartilage, with formation of chondrocyte clusters adjacent to a zone of cartilage necrosis. In wound repair, spatially and temporally controlled expression of matrix metalloproteinases and their inhibitors have been implicated in proteolytic degradation of damaged extracellular matrix components, but the sequence of events following damage to cartilage is unknown. To determine this sequence, we studied the distribution of matrix metalloproteinases and their inhibitors during early in vivo repair of partial-thickness defects in pig articular cartilage.

Methods: With use of a model that elicits the ingrowth of mesenchymal cells into partial-thickness defects, partial-thickness defects were created in knee joint cartilage. The distributions of matrix metalloproteinase-1, 2, 3, 9, 13, and 14; tissue inhibitors of metalloproteinase-1 and 2; and the neoepitope DIPEN341 specifically generated following matrix metalloproteinase cleavage of aggrecan were determined by immunolocalization of repair tissue and surrounding cartilage excised from immature pigs during the first eight weeks of repair and from adult minipigs at eight days and three weeks.

Results: Synthesis of matrix metalloproteinase-13 was usually confined to hypertrophic chondrocytes in immature cartilage and to the radial zone in adult cartilage. Following injury, strong induction of matrix metalloproteinase-13 synthesis was observed in chondrocyte clusters surrounding lesions in all of the animals. The migration of macrophages into defects was prominent at two and eight days, with synthesis and deposition of matrix metalloproteinase-9 onto damaged cartilage matrix and newly synthesized matrix in the defect. The DIPEN341 neoepitope was localized to damaged cartilage matrix at eight days and six weeks, indicating partial degradation of aggrecan. Focal synthesis of matrix metalloproteinase-1, 3, and 14 and of tissue inhibitor of metalloproteinase-1 occurred at later times, suggesting continuous remodeling of the increasingly compact repair tissue.

Conclusions: The expression of matrix metalloproteinase-13 by normal hypertrophic chondrocytes and the induction of synthesis in chondrocyte clusters adjacent to the zone of cartilage necrosis suggest that this enzyme participates in the pericellular proteolysis required for lacunar expansion. The localization of matrix metalloproteinase-9 to damaged cartilage matrix suggested matrix proteolysis, which was confirmed with DIPEN341 localization. Reduced matrix metachromasia persisted and was colocalized with DIPEN341 at six weeks. However, under the conditions investigated, there was only limited proteolytic degradation in the zone of cartilage necrosis. This may render the zone mechanically weakened, thereby contributing to subsequent instability of the region, and may form a barrier to integration of repair tissue with viable cartilage.

Clinical Relevance: Osteoarthritis initially involves the superficial layers of cartilage. The development of procedures to promote the healing or repair of early defects will have major advantages in terms of disease alleviation as well as economic importance. Identification of the enzymes involved in the early repair of partial-thickness defects in articular cartilage is clinically relevant because proteolysis of damaged matrix has to take place in order for repair tissue to integrate with surrounding healthy cartilage.


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