The effects of short- and long-term load-controlled compression on the levels of aggrecan mRNA have been determined. Results show that a compressive stress of 0.1 MPa on bovine articular cartilage explants for 1, 4, 12, and 24 h produces a transient up-regulation of aggrecan mRNA synthesis. At 1 h, aggrecan mRNA levels in loaded explants were increased 3.2-fold compared to control explants. At longer times (≥4 h), the levels of aggrecan mRNA returned to baseline values or stayed slightly higher. There is a dose dependence in the response of the explant to increasing levels of compressive stress (0–0.5 MPa) for 1 h. Aggrecan mRNA levels increased 2- to 3-fold at 0–0.25 MPa. At 0.5 MPa, the level of aggrecan mRNA was lower than those at 0.1 and 0.25 MPa. This dose-dependent effect suggests a reversal of the stimulatory effects of compression on aggrecan gene expression at higher loads. After 24 h of compression, the levels of aggrecan mRNA in explants subjected to any of the stress levels were not significantly different from those in control explants. The stimulatory effect of 0.1 MPa compressive stress on aggrecan mRNA levels was blocked by Rp-cAMP and U-73122, indicating the involvement of the classical signal transduction pathways in the mechanical modulation of aggrecan gene expression. The responses of link protein mRNA to compression paralleled those of aggrecan, while there was no significant change in expression of the gene for the housekeeping protein elongation factor-1α. The results indicate that articular cartilage chondrocytes can respond to short-term compressive loads by transiently up-regulating expression of the aggrecan gene. The fact that long-term compression did not significantly alter aggrecan mRNA levels suggests that previously observed inhibitory effects of prolonged static compression on proteoglycan synthesis in articular cartilage may be, for the most part, mediated through mechanisms other than suppression of aggrecan mRNA levels.