PROSTAGLANDIN E(2) STIMULATES INCORPORATION OF PROLINE INTO COLLAGENASE DIGESTIBLE PROTEINS IN HUMAN ARTICULAR CHONDROCYTES - IDENTIFICATION OF AN EFFECTOR AUTOCRINE LOOP INVOLVING INSULIN-LIKE GROWTH-FACTOR-I

Prostaglandin E(2) (PGE(2)) stimulates collagen gene promoter activity in transfected human chondrocytes though no canonical cyclic AMP (cAM P) response element has been yet identified. Human insulin-like growth factor-1 (IGF-1) induces an increase in collagen type II expression a nd synthesis in chondrocytes. Since our preliminary data suggested tha t PGE(2) can stimulate IGF-(1) release from human articular chondrocyt es, we examined whether the eicosanoid could influence collagen synthe sis and whether the effect was mediated by IGF-1. Incubation of primar y cultures of human articular chondrocytes with increasing concentrati ons of PGE(2) resulted in a dose-dependent (ANOVA, F = 51.62, P < 0.00 01, ii = 5) and saturable increase in the synthesis and release of IGF -1 and expression of IGF-1 mRNA. At relatively low concentrations (30 pmol/l to 30 nmol/l), PGE(2) stimulated an increase in the incorporati on of [H-3]proline into collagenase digestible protein (CDP) (P < 0.01 , n = 5) whereas at high levels (300 nmol/l to 3 mu mol/l) of the eico sanoid, incorporation diminished precipitously. Human IGF-1 mimicked t he effects of low PGE(2) concentrations by stimulating in a dose-depen dent (ANOVA, F = 31.65, P < 0.001; n = 3) and saturable fashion the in corporation of [H-3]proline into CDP although the magnitude of the res ponse induced by IGF-1 was far greater (3.5-fold). An IGF-1 receptor b locking antibody completely abrogated the IGF-1 induced response sugge sting that the effect was specifically IGF-1 receptor mediated. Furthe rmore, the PGE(2)-induced increase in [H-3]proline incorporation into CDP was inhibited (63%, P < 0.001, ii = 7) by the addition to the cult ure medium of an anti-IGF-1 antibody, We conclude that PGE(2) may act as a secretagogue of IGF-1 and that the latter growth factor may media te, via an autocrine loop and the IGF-1 receptor, at least some of the anabolic effects of the eicosanoid on cartilage metabolism.