Maturational changes in superficial zone chondrocytes

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DESCRIPTION (provided by applicant): Intra-articular injuries in adults are clinically problematic, as cartilage has a limited capacity to heal. While cartilage healing is age-related the factors contributing to the superior healing capacities in skeletally immature individuals is unknown. Previously, we have used genetically modified chondrocytes over expressing bone morphogenetic protein-7 (BMP-7) to test whether increasing chondrocyte matrix synthesis could enhance cartilage repair. While genetic modification did increase type II collagen and proteoglycan synthesis in the chondrocytes, in vivo, they were unable to integrate to the host cartilage so that no long-term benefit was found. At the terminal time point of our study, fibro-cartilage repair, derived from host cells was observed. While this tissue had hyaline-like qualities in the deep zone, the upper zone and articular surface were severely abnormal with fibrous tissue that was not integrated to the surrounding tissue. Previous studies have shown that chondrocytes from close to the articular surface of cartilage have a distinct phenotype versus those in the deeper zones. Superficial (S) chondrocytes modulate matrix synthesis by deep zone (D) chondrocytes and produce higher levels of matrix degrading enzymes. We have shown in preliminary studies that S chondrocytes also have a greater capacity to migrate than D chondrocytes. The purpose of this investigation is to test whether S chondrocytes may be better than D chondrocytes in supporting integrative cartilage repair. To test this hypothesis, we will first optimize the culture and propagation of S chondrocytes. Ability to migrate and express matrix metallo-proteases will be used as surrogate indicators of remodeling capacity. Cartilage repair by S versus D chondrocytes will be performed using an in vitro model previously established by our group. As cartilage repair occurs more readily in skeletally immature individuals than in adults, S and D chondrocytes from immature or aged steers will be compared. In developing optimized culture conditions for S chondrocytes, differences in matrix attachment and growth factor sensitivity between immature and aged S and D chondrocytes will be tested. Whereas most cell based cartilage repair strategies, including previous studies by our group, have focused on increasing chondrocyte matrix synthesis, these studies will investigate whether enhanced remodeling by chondrocytes may be more important for integrative cartilage repair.