Premium
Retinoids directly activate the collagen X promoter in prehypertrophic chondrocytes through a distal retinoic acid response element
Author(s) -
Cohen Arthur J.,
Lassová Luisa,
Golden Eleanor B.,
Niu Zeling,
Adams Sherrill L.
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20937
Subject(s) - retinoic acid , chondrocyte , microbiology and biotechnology , retinoid , retinoic acid receptor , transcription (linguistics) , endochondral ossification , transcription factor , biology , response element , chondrogenesis , retinoid x receptor , runx2 , extracellular matrix , tretinoin , chemistry , gene expression , medicine , promoter , cartilage , gene , biochemistry , anatomy , mesenchymal stem cell , nuclear receptor , philosophy , linguistics
Retinoids are essential for the terminal differentiation of chondrocytes during endochondral bone formation. This maturation process is characterized by increased cell size, expression of a unique extracellular matrix protein, collagen X, and eventually by mineralization of the matrix. Retinoids stimulate chondrocyte maturation in cultured cells and experimental animals, as well as in clinical studies of synthetic retinoids; furthermore, retinoid antagonists prevent chondrocyte maturation in vivo. However, the mechanisms by which retinoids regulate this process are poorly understood. We and others showed previously that retinoic acid (RA) stimulates expression of genes encoding bone morphogenetic proteins (BMPs), suggesting that retinoid effects on chondrocyte maturation may be indirect. However, we now show that RA also directly stimulates transcription of the collagen X gene promoter. We have identified three RA response element (RARE) half‐sites in the promoter, located 2,600 nucleotides upstream from the transcription start site. These three half‐sites function as two overlapping RAREs that share the middle half‐site. Ablation of the middle half‐site destroys both elements, abolishing RA receptor (RAR) binding and drastically decreasing RA stimulation of transcription. Ablation of each of the other two half‐sites destroys only one RARE, resulting in an intermediate level of RAR binding and transcriptional stimulation. These results, together with our previously published data, indicate that retinoids stimulate collagen X transcription both directly, through activation of RARs, and indirectly, through increased BMP production. J. Cell. Biochem. © 2006 Wiley‐Liss, Inc.