Immunolocalization of matrix metalloproteinases in partial-thickness defects in pig articular cartilage - A preliminary report

Rm. Hembry et al., Immunolocalization of matrix metalloproteinases in partial-thickness defects in pig articular cartilage - A preliminary report, J BONE-AM V, 83A(6), 2001, pp. 826-838
Citations number
Categorie Soggetti
Ortopedics, Rehabilitation & Sport Medicine","da verificare
Journal title
ISSN journal
0021-9355 → ACNP
Year of publication
826 - 838
SICI code
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 rep air, spatially and temporally controlled expression of matrix metalloprotei nases and their inhibitors have been implicated in proteolytic degradation of damaged extracellular matrix components, but the sequence of events foll owing damage to cartilage is unknown. To determine this sequence, we studie d the distribution of matrix metalloproteinases and their inhibitors during early in vivo repair of partial-thickness defects in pig articular cartila ge. 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 ne oepitope DIPEN341 specifically generated following matrix metalloproteinase cleavage of aggrecan were determined by immunolocalization of repair tissu e and surrounding cartilage excised from immature pigs during the first eig ht weeks of repair and from adult minipigs at eight days and three weeks. Results: Synthesis of matrix metalloproteinase-13 was usually confined to h ypertrophic chondrocytes in immature cartilage and to the radial zone in ad ult cartilage. Following injury, strong induction of matrix metalloproteina se-13 synthesis was observed in chondrocyte clusters surrounding lesions in ail of the animals. The migration of macrophages into defects was prominen t at two and eight days, with synthesis and deposition of matrix metallopro teinase-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. Fo cal synthesis of matrix metalloproteinase-1, 3, and 14 and of tissue inhibi tor of metalloproteinase-1 occurred at later times, suggesting continuous r emodeling ai the increasingly compact repair tissue. Conclusions: The expression of matrix metalloproteinase-13 by normal hypert rophic chondrocytes and the induction of synthesis in chondrocyte clusters adjacent to the zone of cartilage necrosis suggest that this enzyme partici pates in the pericellular proteolysis required for lacunar expansion. The l ocalization of matrix metalloproteinase-9 to damaged cartilage matrix sugge sted matrix proteolysis, which was confirmed with DIPEN341 localization. Re duced matrix metachromasia persisted and was colocalized with DIPEN341 at s ix weeks. However, under the conditions investigated, there was only limite d proteolytic degradation in the zone of cartilage necrosis. This may rende r the zone mechanically weakened, thereby contributing to subsequent instab ility of the region, and may form a barrier to integration of repair tissue with viable cartilage. Clinical Relevance: Osteoarthritis initially involves the superficial layer s of cartilage. The development of procedures to promote the healing or rep air of early defects will have major advantages in terms of disease allevia tion 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 plac e in order for repair tissue to integrate with surrounding healthy cartilag e.