The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice.
The B cell lymphoma 2 (Bcl-2) family member Bcl-xL has a well-characterized antiapoptotic function in lymphoid cells. However, its functions in other cells--including osteoclasts, which are of hematopoietic origin--and other cellular processes remain unknown. Here we report an unexpected function of Bcl-xL in attenuating the bone-resorbing activity of osteoclasts in mice. To investigate the role of Bcl-xL in osteoclasts, we generated mice with osteoclast-specific conditional deletion of Bcl-x (referred to herein as Bcl-x cKO mice) by mating Bcl-xfl/fl mice with mice in which the gene encoding the Cre recombinase has been knocked into the cathepsin K locus and specifically expressed in mature osteoclasts. Although the Bcl-x cKO mice grew normally with no apparent morphological abnormalities, they developed substantial osteopenia at 1 year of age, which was caused by increased bone resorption. Bcl-x deficiency increased the bone-resorbing activity of osteoclasts despite their high susceptibility to apoptosis, whereas Bcl-xL overexpression produced the opposite effect. In addition, Bcl-x cKO osteoclasts displayed increased c-Src activity, which was linked to increased levels of vitronectin and fibronectin expression. These results suggest that Bcl-xL attenuates osteoclastic bone-resorbing activity through the decreased production of ECM proteins, such as vitronectin and fibronectin, and thus provide evidence for what we believe to be a novel cellular function of Bcl-xL.
Iwasawa
Mitsuyasu
M
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Miyazaki
Tsuyoshi
T
Nagase
Yuichi
Y
Akiyama
Toru
T
Kadono
Yuho
Y
Nakamura
Masaki
M
Oshima
Yasushi
Y
Yasui
Tetsuro
T
Matsumoto
Takumi
T
Nakamura
Takashi
T
Kato
Shigeaki
S
Hennighausen
Lothar
L
Nakamura
Kozo
K
Tanaka
Sakae
S
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000033:anatomy & histology / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D002470:Cell Survival; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009596:Nitrophenols / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019061:src-Family Kinases
C501332:ABT-737; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D005419:Flavonoids; D009596:Nitrophenols; D010879:Piperazines; D053245:RANK Ligand; D013449:Sulfonamides; C505689:Tnfsf11 protein, mouse; D051020:bcl-X Protein; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one