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The Journal of Bone and Joint Surgery (American) 85:29-33 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.

Basic Science

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

Sherrill L. Adams, PhD, Kim M. Pallante, BS, Zeling Niu, BS, Arthur J. Cohen, PhD, Jane Lu, BS and Phoebe S. LeBoy, PhD

Corresponding author: Sherrill L. Adams, PhD
University of Pennsylvania School of Dental Medicine, 240 South 40th Street, Philadelphia, PA 19104-6030. E-mail address: sherri{at}biochem.dental.upenn.edu

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the National Institutes of Health (NIH Grants AR48214 [S.L.A.] and AR40075 [P.S.L.]). None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated. BMP-2 was provided by Genetics Institute, Cambridge, Massachusetts.

Abstract

Background: Chondrocyte 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.

Methods: Prehypertrophic 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.

Results: The 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.

Conclusions: These 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 Relevance: Retinoids 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.


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