Increased proteoglycan synthesis in cartilage in experimental canine osteoarthritis does not reflect a permanent change in chondrocyte phenotype

Abstract

Objective. To determine whether chondrocytes in early experimental osteoarthritic (OA) cartilage continue to show increased synthesis and turnover of proteoglycans (PGs) during explant culture. A comparison was also made between the responsiveness of experimental OA and control cartilage to interleukin-lf3 (IL-1p) and tumor necrosis factor a (TNFa) after 1 day and 3 days in culture.Methods. OA was induced in mature animals by sectioning of the anterior cruciate ligament followed by 3 months of normal exercise. PG synthesis in the articular cartilage was determined by measuring "S-sulfate incorporation during explant culture over 1-3 days. Inhibition of PG synthesis was also determined with various concentrations of IL-lfl and TNFa after 1 and 3 days in culture. PGs extracted from the articular cartilage over 1-3 days in culture were examined by agarosepolyacrylamide gel electrophoresis.Results. Up to 24 hours after excision from the joint, PG synthesis was higher in experimental OA cartilage than in control cartilage. It was also less sensitive to inhibition by TNFa. These differences were no longer detected after 48-72 hours in culture. There were no changes in the relative proportions of aggrecan and decoridbiglycan extracted from and synthesized by control and experimental OA cartilage over the 3 days in culture.Conclusion. Previous results indicated that PG synthesis and turnover in articular cartilage was increased for many months after induction of experimen- ____tal OA. Our present results show that the enhanced rate of PG synthesis and turnover were evident in freshly explanted tissue, but the differences were lost over 3 days in culture. A decreased responsiveness to TNFa was also lost. The hypermetabolic activity of experimental OA chondrocytes was thus reversible and not a permanent change in chondrocyte phenotype.The canine model of experimental osteoarthritis (OA) described by Pond and Nuki ( l ) , in which OA changes are induced by resection of the anterior cruciate ligament of the stifle joint, has features which resemble those of naturally occurring canine OA and can progress to exhibit many features of advanced OA in humans (2,3). Damage and eventual loss of the articular cartilage is a frequent outcome of natural and experimental OA, and this experimental model provides an opportunity to investigate the early changes in articular cartilage that precede its damage.Work from our laboratory and others has shown that some of the earliest changes in the articular cartilage are both increased rates of matrix protein synthesis (4-7) and increased rates of degradation of matrix components (8-1 l), which suggest that there is hyperactivity of the chondrocytes. The newly synthesized proteoglycans (PGs) exhibit qualitative differences from those of control cartilage as do those released from experimental OA cartilage (9). The factors which cause these changes are not known. It is also not established if these cellular changes are reversible or reflect the emergence of the "OA chondrocyte." In experimenta...

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