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J. Biol. Chem., Vol. 281, Issue 37, 27229-27241, September 15, 2006

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Pro-inflammatory Cytokine Tumor Necrosis Factor- Induces Bone Morphogenetic Protein-2 in Chondrocytes via mRNA Stabilization and Transcriptional Up-regulation^*

Naoshi Fukui¹, Yasuko Ikeda, Toshiyuki Ohnuki, Atsuhiko Hikita, Sakae Tanaka, Shoji Yamane, Ryuji Suzuki, Linda J. Sandell^¶, and Takahiro Ochi

From the Department of Pathomechanisms, Clinical Research Center, National Hospital Organization Sagamihara Hospital, Sagamihara, Kanagawa 228-8522, Japan, the Department of Orthopaedic Surgery, Faculty of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, and the ^¶Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110

In articular chondrocytes, the inflammatory cytokine tumor necrosis factor- (TNF-) induces the expression of bone morphogenetic protein-2 (BMP-2), a growth factor known to be involved in the induction of cartilage and bone. A study was performed to clarify the mechanism(s) underlying the induction of BMP-2 in chondrogenic ATDC5 cells and primary cultured adult human articular chondrocytes. In ATDC5 cells, the endogenous BMP-2 expression was consistently low throughout the process of chondrogenic differentiation, and TNF- induced BMP-2 expression only after the cells acquired the chondrogenic phenotype. The results of nuclear run-off assay and cycloheximide treatment consistently indicated that ATDC5 cells acquire the capacity to synthesize BMP-2 mRNA in the nuclei during the differentiation process. In an attempt to explain the discrepancy between the active nuclear mRNA synthesis and the observed low expression level in differentiated ATDC5 cells, the stability of BMP-2 mRNA was evaluated, and the cells were found to regulate the expression of BMP-2 at the post-transcriptional level. Human chondrocytes were confirmed to have a similar post-transcriptional regulation. The result of 3'-rapid amplification of cDNA end revealed that both human and mouse BMP-2 mRNAs contain multiple pentameric AUUUA motifs in a conserved manner in the 3'-untranslated regions, and transient transfection experiments demonstrated that TNF- increases the stability of BMP-2 mRNA through the pentameric motifs. Further experiments revealed that TNF- modulates mRNA stability via p38 signal transduction pathway, whereas the cytokine also augmented the expression of BMP-2 through transcriptional up-regulation via the transcriptional factor NF-B.

Received for publication, April 10, 2006 , and in revised form, June 12, 2006.

^* This work was supported in part by Grants-in-aid from the Japan Society for the Promotion of Science (Grant 15390467), the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant 16659416), the Mitsui Life Social Welfare Foundation, the Nakatomi Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-42-742-8311; Fax: 81-42-742-7990; E-mail: n-fukui{at}sagamihara-hosp.gr.jp.

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