Cartilage-derived retinoic acid-sensitive protein (CD-RAPCartilage-derived retinoic acid-sensitive protein (CD-RAP) 1 is a small, secreted matrix protein expressed in developing and adult cartilage and by chondrocytes in culture (1). It was originally cloned as an mRNA co-regulated with Col2a1 in chondrocytes and provides a reliable model for chondrocyte gene transcription (2). Melanoma inhibitory activity (MIA), the human homologue of Cd-rap, was isolated independently from a cell line derived from a brain metastasis of a human melanoma (3). Cd-rap/MIA is expressed by various tumor cells including melanoma, chondrosarcoma, and breast cancer, but its physiological expression is restricted primarily to cartilage (4). The protein structure of Cd-rap/MIA showed that it is a Src homologue 3 domain, a feature that is unique for an extracellular protein. We have shown previously that the expression of Cdrap is repressed by interleukin 1␤ (IL-1␤) (5), a major cytokine that mediates the inflammatory reaction, and is considered to play an important role in the cartilage degradation observed in osteoarthritis and rheumatoid arthritis. The transcription factor C/EBP␤ plays an important role in the IL-1␤-induced repression of both Cd-rap and Col2a1 (6).C/EBPs are a family of transcription factors that contain a highly conserved, basic leucine zipper domain at the carboxyl terminus that is involved in dimerization and DNA binding. C/EBP␤ mRNA can produce at least three isoforms by alternative initiation of translation, 38 kDa (liver-enriched activated protein (LAP-FL)), 35 kDa (LAP), and 20 kDa (liver-enriched inhibitory protein (LIP)), with the LAP and the LIP forms being the major polypeptides produced in cells (7). These two proteins share the 145 carboxyl-terminal amino acids that contain the basic DNA-binding domain and the leucine zipper dimerization helix (7) but differ at the amino terminus. IL-1␤ treatment of lung interstitial cells or rat chondrosarcoma (RCS) cells increase C/EBP␤ mRNA and protein levels, including LAP and LIP (6,8), and all forms of C/EBP␤ and a related protein C/EBP␦ repress Cd-rap gene expression. Col2a1 is also repressed by C/EBP␤ and C/EBP␦ (6).Sox9, a high mobility group domain transcription factor, has been identified as a key regulator in chondrocyte differentiation (9). Sox9 is a member of a large family of proteins that harbor a DNA-binding domain with Ͼ50% similarly to that of sex-determining region Y, the testis-determining gene in mammals (10). Sox9 binds to and controls transcription factor of the Col2a1 (11) and Cd-rap (12) genes.Co-activators CBP and p300 were originally identified as proteins that bind to the adenoviral E1A and the cAMP-response element-binding protein (CREB), respectively (10, 13). The CBP/p300 genes are conserved in a variety of multicellular organisms, from worms to humans, and are very similar in structure and function. The CBP/p300 proteins are very large transcriptional co-regulators that participate in the activities of many different transcription factors ...

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