HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 39, 26499-26508, September 26, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/39/26499    most recent M800933200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Oshima, Y. Articles by Tanaka, S. Search for Related Content PubMed PubMed Citation Articles by Oshima, Y. Articles by Tanaka, S. Social Bookmarking                      What's this?

Pivotal Role of Bcl-2 Family Proteins in the Regulation of Chondrocyte Apoptosis^*

Yasushi Oshima, Toru Akiyama, Atsuhiko Hikita, Mitsuyasu Iwasawa, Yuichi Nagase, Masaki Nakamura, Hidetoshi Wakeyama, Naohiro Kawamura, Toshiyuki Ikeda, Ung-il Chung^¶, Lothar Hennighausen^||, Hiroshi Kawaguchi, Kozo Nakamura, and Sakae Tanaka¹

From the Department of Orthopaedic Surgery, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, the Department of Pathomechanisms, Clinical Research Center, National Hospital Organization Sagamihara Hospital, 18-1 Sakuradai, Sagamihara, Kanagawa 228-8522, Japan, ^¶Center for Disease Biology and Integrative Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and ^||Laboratory of Genetics and Physiology, National Institutes of Health, Bethesda, Maryland 20892-2560

During endochondral ossification, chondrocytes undergo hypertrophic differentiation and die by apoptosis. The level of inorganic phosphate (P_i) elevates at the site of cartilage mineralization, and when chondrocytes were treated with P_i, they underwent rapid apoptosis. Gene silencing of the proapoptotic Bcl-2 homology 3-only molecule bnip3 significantly suppressed P_i-induced apoptosis. Conversely, overexpression of Bcl-xL suppressed, and its knockdown promoted, the apoptosis of chondrocytes. Bnip3 was associated with Bcl-xL in chondrocytes stimulated with P_i. Bcl-xL was expressed uniformly in the growth plate chondrocytes, whereas Bnip3 expression was exclusively localized in the hypertrophic chondrocytes. Finally, we generated chondrocyte-specific bcl-x knock-out mice using the Cre-loxP recombination system, and we provided evidence that the hypertrophic chondrocyte layer was shortened in those mice because of an increased apoptosis of prehypertrophic and hypertrophic chondrocytes, with the mice afflicted with dwarfism as a result. These results suggest the pivotal role of Bcl-2 family members in the regulation of chondrocyte apoptosis.

Received for publication, February 5, 2008 , and in revised form, July 16, 2008.

^* This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and health science research grants from the Ministry of Health, Labor, and Welfare of Japan (to S. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Hongo7-3-1, Bunkyoku, Tokyo113-0033, Japan. Tel.: 81-3-3815-5415, ext. 33376; Fax: 81-3-3818-4082; E-mail: TANAKAS-ORT{at}h.u-tokyo.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?