Pleiotrophin inhibits chondrocyte proliferation and stimulates proteoglycan synthesis in mature bovine cartilage

Pleiotrophin (PTN) is a secreted heparin-binding, developmentally regulated protein that is found in abundance in fetal, but not mature, cartilage. SD S-page and glycosaminoglycan (GAG) analysis of sulfate-radiolabeled proteog lycans isolated from the medium of mature cultured chondrocytes treated wit h PTN showed a threefold increase in the levels of proteoglycan synthesis. In contrast, in cultures of fetal chondrocytes, no changes in proteoglycan synthesis were observed. Thymidine incorporation experiments showed a dose- dependent decrease in proliferation of treated cells compared with control cultures, suggesting that pleiotrophin had an inhibitory effect on growth o f chondrocytes. Neither FGF or heparin reversed the inhibitory effect of PT N. Capillary electrophoresis of chondroitinase ABC-digested proteoglycans i solated from mature chondrocytes showed 2-4-fold increases in the amounts o f the 4S- and 6S-substituted GAG chains for the PTN-treated chondrocytes. N orthern analysis showed a twofold upregulation in the mRNA levels of biglyc an and collagen type II, but no difference in the message levels for decori n and aggrecan. These results establish that PTN inhibits cell proliferatio n, while stimulating the synthesis of proteoglycans in mature chondrocytes in vitro, suggesting that PTN may act directly or indirectly to regulate gr owth and proteoglycan synthesis in the developing matrix of fetal cartilage . (C) 1999 Published by Elsevier Science B.V./International Society of Matr ix Biology. All rights reserved.