Stimulation of Type-X Collagen Gene Transcription by Retinoids Occurs in Part Through the BMP Signaling Pathway

BackgroundChondrocyte maturation and hypertrophy during endochondral bone formation are stimulated by both retinoids and bone morphogenetic proteins (BMPs). The type-X collagen gene, which is expressed only in hypertrophic chondrocytes, provides an excellent marker for chondrocyte maturation. We pre...

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Published in:Journal of bone and joint surgery. American volume 2003-01, Vol.85 (suppl_3 Suppl 3), p.29-33
Main Authors: Adams, Sherrill L, Pallante, Kim M, Niu, Zeling, Cohen, Arthur J, Lu, Jane, LeBoy, Phoebe S
Format: Article
Language:English
Subjects:
Animals
Bone Morphogenetic Protein 2
Bone Morphogenetic Protein 4
Bone Morphogenetic Protein 6
Bone Morphogenetic Proteins - genetics
Bone Morphogenetic Proteins - physiology
Cell Differentiation - drug effects
Cell Differentiation - genetics
Cells, Cultured
Chick Embryo
Chondrocytes - cytology
Collagen Type X - genetics
Gene Expression Regulation - drug effects
Osteogenesis - drug effects
Osteogenesis - genetics
Promoter Regions, Genetic - genetics
Retinoids - pharmacology
RNA, Messenger - genetics
Signal Transduction - drug effects
Transcription, Genetic - drug effects
Transforming Growth Factor beta
Tretinoin - pharmacology
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Summary:BackgroundChondrocyte maturation and hypertrophy during endochondral bone formation are stimulated by both retinoids and bone morphogenetic proteins (BMPs). The type-X collagen gene, which is expressed only in hypertrophic chondrocytes, provides an excellent marker for chondrocyte maturation. We previously identified a 651-base-pair region of the type-X collagen promoter that is essential for its activation by BMP. We examined the relationship between the retinoid and BMP signaling pathways in transcriptional stimulation of the type-X collagen gene to determine whether they act independently or interact to regulate endochondral bone formation.MethodsPrehypertrophic chondrocytes from embryonic chick sterna cultured in the presence or absence of retinoic acid or BMP-2 were transiently transfected with plasmids containing various mutations of the type-X collagen promoter directing expression of a luciferase reporter gene. In addition, real-time polymerase chain reaction was used to examine the effects of retinoic acid on expression of genes encoding BMP-2, 4, and 6.ResultsThe previously identified BMP-responsive region of the type-X collagen promoter also mediated stimulation by physiological concentrations of retinoic acid in prehypertrophic chondrocytes. Systematic deletion mutagenesis of the BMP/retinoid-responsive region of the type-X collagen promoter identified distinct regions that are responsible for promoter stimulation by retinoids and BMP. Retinoic acid rapidly and dramatically stimulated accumulation of BMP-2 and BMP-6 messenger RNAs.ConclusionsThese results suggest that, while retinoic acid appears to stimulate type-X collagen gene transcription in part by stimulating the BMP signaling pathway, it also acts in part through mechanisms that are independent of BMP.Clinical RelevanceRetinoids are essential for chondrocyte maturation during endochondral bone formation, but at high concentrations vitamin A is a potent teratogen; thus, both excessive and deficient vitamin A cause skeletal abnormalities by mechanisms that are not well understood. Since synthetic derivatives of vitamin A are widely used therapeutic agents for the treatment of several types of diseases, it is important to understand their effects on endochondral bone formation.
ISSN:0021-9355
1535-1386
DOI:10.2106/00004623-200300003-00006