Current data provide compelling evidence that the pH of the interstitial fluid of cartilage is an important determinant of the metabolic activity of chondrocytes, and this has served as the basis for a mechanistic proposal whereby chondrocytes could sense mechanical compression. The objective of the current study was to test this hypothesis further by examining biosynthetic activity in cartilage as a function of glycosaminoglycan content, which is the major determinant of interstitial pH. On the basis of previous data, increased biosynthetic activity would be anticipated to correlate with a decreased glycosaminoglycan content and an elevated interstitial pH. In contrast to our expectations, we found that the biosynthetic activity (monitored by measurement of incorporation of sulfate and proline) was positively correlated with the glycosaminoglycan content of tissue. These results raise doubt as to whether interstitial pH provides a dominant mechanism for controlling the metabolism of chondrocytes.