title: Modulation of limb bud chondrogenesis by retinoic acid and retinoic acid receptors.
abstract: An excess of retinoic acid (RA) in the mouse embryo in utero produces hypochondrogenesis and severe limb bone deformities. Since one of the RA receptors--RAR-beta 2, is specifically induced in the limb bud cells upon treatment of embryos with teratogenic doses of RA, we investigated if this receptor played a role in teratogenesis by regulating the process of chondrogenesis. In micromass cultures of mouse limb bud mesenchymal cells, we found that a downregulation of RAR-beta 2 as well as several other RAR isoforms by supplementation of the culture medium with specific oligodeoxynucleotides stimulated chondrogenesis: cartilage nodule number, sulfated proteoglycans, and synthesis of collagen type IIB were all enhanced in a dose-dependent manner. However, only the antisense RAR-beta 2 probe efficiently prevented the strong inhibitory effects of exogenous RA on chondrogenesis in these cells. The data suggest that the RAR-RA complexes play a role in position-dependent patterning of the limb skeleton in normal development and that, in particular, RAR-beta 2 serves to prevent the mesenchymal cells from expressing their chondrogenic bias. Our results further strengthen the argument that RA-dependent elevation in RAR-beta 2 levels plays a unique role in RA-induced teratogenesis.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: D R
authors.initials: DR
authors.lastname: Soprano
authors.forename: S W
authors.initials: SW
authors.lastname: Li
authors.forename: K J
authors.initials: KJ
authors.lastname: Soprano
authors.forename: J D
authors.initials: JD
authors.lastname: Penner
authors.forename: M
authors.initials: M
authors.lastname: Gyda
authors.forename: D M
authors.initials: DM
authors.lastname: Kochhar
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000196:embryology*; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D017931:DNA Primers; D015536:Down-Regulation; D018878:Limb Buds / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009924:Organ Culture Techniques; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D013431:Sulfates / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology*; D014617:Vacuoles / Q000648:ultrastructure; D000097768:Retinoic Acid Receptor gamma
chemical_list: D003094:Collagen; D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D013431:Sulfates; D014157:Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse; C082925:retinoic acid receptor beta