Prostaglandin E2 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 E2 (PGE2) stimulates collagen gene promoter activity in transfected human chondrocytes though no canonical cyclic AMP (cAMP) response element has been yet identified. Human insulin-like growth factor-1 (IGF-1) induces an increase in collagen type II expression and synthesis in chondrocytes. Since our preliminary data suggested that PGE2 can stimulate IGF-1 release from human articular chondrocytes, we examined whether the eicosanoid could influence collagen synthesis and whether the effect was mediated by IGF-1. Incubation of primary cultures of human articular chondrocytes with increasing concentrations of PGE2 resulted in a dose-dependent (ANOVA, F= 51.62, P < 0.0001, n = 5) and saturable increase in the synthesis and release of IGF-1 and expression of IGF-1 mRNA. At relatively low concentrations (30 pmol/1 to 30 nmol/l), PGE2 stimulated an increase in the incorporation of [3H]proline into collagenase digestible protein (CDP) (P < 0.01, n = 5) whereas at high levels (300 nmol/l to 3 micromol/l) of the eicosanoid, incorporation diminished precipitously. Human IGF-1 mimicked the effects of low PGE2 concentrations by stimulating in a dose-dependent (ANOVA, F= 31.65, P < 0.001, n = 3) and saturable fashion the incorporation of [3H]proline into CDP although the magnitude of the response induced by IGF-1 was far greater (3.5-fold). An IGF-1 receptor blocking antibody completely abrogated the IGF-1 induced response suggesting that the effect was specifically IGF-1 receptor mediated. Furthermore, the PGE2-induced increase in [3H]proline incorporation into CDP was inhibited (63%, P < 0.001, n = 7) by the addition to the culture medium of an anti-IGF-1 antibody. We conclude that PGE2 may act as a secretagogue of IGF-1 and that the latter growth factor may mediate, via an autocrine loop and the IGF-1 receptor, at least some of the anabolic effects of the eicosanoid on cartilage metabolism.
Department of Medicine, University of Montreal, Quebec, Canada.
J A
JA
Di Battista
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S
Doré
J
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Martel-Pelletier
J P
JP
Pelletier
D000328:Adult; D000704:Analysis of Variance; D015152:Blotting, Northern; D000001:Calcimycin / Q000494:pharmacology; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D017364:Collagenases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000378:metabolism*; D011458:Prostaglandins E / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic
D011458:Prostaglandins E; D012333:RNA, Messenger; D000001:Calcimycin; D015759:Ionomycin; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D011392:Proline; D017364:Collagenases