Pivotal role of Bcl-2 family proteins in the regulation of chondrocyte apoptosis.
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.
Oshima
Yasushi
Y
Department of Orthopaedic Surgery, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Akiyama
Toru
T
Hikita
Atsuhiko
A
Iwasawa
Mitsuyasu
M
Nagase
Yuichi
Y
Nakamura
Masaki
M
Wakeyama
Hidetoshi
H
Kawamura
Naohiro
N
Ikeda
Toshiyuki
T
Chung
Ung-il
UI
Hennighausen
Lothar
L
Kawaguchi
Hiroshi
H
Nakamura
Kozo
K
Tanaka
Sakae
S
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*
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