12746314

pubmed:Citation

6

Whereas bone morphogenetic protein (BMP)-signaling events induce maturational characteristics in vitro, recent evidence suggests that the effects of other regulators might be mediated through BMP-signaling events. The present study examines the mechanism through which retinoic acid (RA) stimulates differentiation in chicken embryonic caudal sternal chondrocyte cultures. Both RA and BMP-2 induced expression of the chondrocyte maturational marker, colX, in chondrocyte cultures by 8 d. Though the RA effect was small, it synergistically enhanced the effect of BMP-2 on colX and phosphatase activity. Inhibition of either RA or BMP signaling, with selective inhibitors, interfered with the inductive effects of these agents but also inhibited the complementary pathway, demonstrating a codependence of RA and BMP signaling during chondrocyte maturation. BMP-2 did not enhance the effects of RA on an RA-responsive reporter construct, but RA enhanced basal activity and synergistically enhanced BMP-2 stimulation of the BMP-responsive chicken type X collagen reporter. A similar synergistic interaction between RA and BMP-2 was observed on colX expression. RA did not increase the expression of the type IA BMP receptor but did markedly up-regulate the expression of Smad1 and Smad5 proteins, important participants in the BMP pathway. Inhibition of RA signaling, with the selective inhibitor AGN 193109, blocked RA-mediated induction of the Smad proteins and chondrocyte differentiation. These findings demonstrate that RA induces the expression of BMP-signaling molecules and enhances BMP effects in chondrocytes.

eng

AIM

MEDLINE

0013-7227

Print

NLM

2514-23

pubmed-meshheading:12746314-Alkaline Phosphatase, pubmed-meshheading:12746314-Animals, pubmed-meshheading:12746314-Antineoplastic Agents, pubmed-meshheading:12746314-Bone Morphogenetic Protein 2, pubmed-meshheading:12746314-Bone Morphogenetic Proteins, pubmed-meshheading:12746314-Cell Differentiation, pubmed-meshheading:12746314-Chick Embryo, pubmed-meshheading:12746314-Chickens, pubmed-meshheading:12746314-Chondrocytes, pubmed-meshheading:12746314-Collagen Type X, pubmed-meshheading:12746314-DNA-Binding Proteins, pubmed-meshheading:12746314-Drug Synergism, pubmed-meshheading:12746314-Phosphoproteins, pubmed-meshheading:12746314-Signal Transduction, pubmed-meshheading:12746314-Smad Proteins, pubmed-meshheading:12746314-Smad5 Protein, pubmed-meshheading:12746314-Sternum, pubmed-meshheading:12746314-Trans-Activators, pubmed-meshheading:12746314-Transforming Growth Factor beta, pubmed-meshheading:12746314-Tretinoin

Retinoic acid stimulates chondrocyte differentiation and enhances bone morphogenetic protein effects through induction of Smad1 and Smad5.

Journal Article, Research Support, U.S. Gov't, P.H.S.