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

Xuefeng Li, Edward M. Schwarz, Michael J. Zuscik, Randy N. Rosier, Andreia M. Ionescu, J. Edward Puzas, Hicham Drissi, Tzong Jen Sheu, Regis J. O'Keefe

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48 Scopus citations

Abstract

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 IABMP 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.

Original languageEnglish
Pages (from-to)2514-2523
Number of pages10
JournalEndocrinology
Volume144
Issue number6
DOIs
StatePublished - Jun 1 2003
Externally publishedYes

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    Li, X., Schwarz, E. M., Zuscik, M. J., Rosier, R. N., Ionescu, A. M., Puzas, J. E., Drissi, H., Sheu, T. J., & O'Keefe, R. J. (2003). Retinoic acid stimulates chondrocyte differentiation and enhances bone morphogenetic protein effects through induction of Smad1 and Smad5. Endocrinology, 144(6), 2514-2523. https://doi.org/10.1210/en.2002-220969