title: Pivotal role of Bcl-2 family proteins in the regulation of chondrocyte apoptosis.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oshima
authors.forename: Toru
authors.initials: T
authors.lastname: Akiyama
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hikita
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Iwasawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nagase
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Wakeyama
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kawamura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Ung-il
authors.initials: UI
authors.lastname: Chung
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C508686:BNip3 protein, mouse; C494812:Bcl2l1 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse